CN1414965A - Sulfonamides and derivatives thereof that modulate the activeity of endothelin - Google Patents

Sulfonamides and derivatives thereof that modulate the activeity of endothelin Download PDF

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CN1414965A
CN1414965A CN00818061A CN00818061A CN1414965A CN 1414965 A CN1414965 A CN 1414965A CN 00818061 A CN00818061 A CN 00818061A CN 00818061 A CN00818061 A CN 00818061A CN 1414965 A CN1414965 A CN 1414965A
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isoxazolyl
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吴成德
乔治·W·霍兰
纳塔莉·布洛克
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Encysive Pharmaceuticals Inc
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Texas Biotechnology Corp
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Abstract

Thienyl-, furyl-, pyrrolyl- and phenylsulfonamides, formulations of pharmaceutically-acceptable derivatives thereof and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, N-(isoxazolyl)thienylsulfonamides, N-(isoxazolyl)-furylsulfonamides, N-(isoxazolyl)pyrrolylsulfonamides and N-(isoxazoly)phenylsulfonamides, formulations thereof and methods using these sulfonamides for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamides or pharmaceutically acceptable derivatives thereof that inhibit the activity of endothelin are also provided.

Description

Adjust active sulphonamide of endothelium peptide and derivative thereof
Related application
The application requires the right of priority of people such as Wu in the 60/174th, No. 104 U.S. Provisional Patent Application of application on December 31st, 1999, and its name is called " adjusting active sulphonamide of endothelium peptide and derivative thereof ".For U.S.'s domestic application and other needs, the content of this temporary patent application is incorporated herein by reference at this.
Invention field
The present invention relates to adjust the active compound of endothelium peptide family peptide.Particularly, the present invention relates to sulphonamide and sulfone amide derivative purposes as endothelium peptide agonists and antagonist.
Background of invention
The blood vessel endothelium peptide discharges many kinds of vaso-active substances, comprises that vasoconstrictor peptide derived from endothelium, endothelium peptide (ET) are (referring to for example: people such as Vanhoutte (1986), Annual Rev.Physiol., 48:307-320; Furchgott and Zawadski (1980), Nature, 288:373-376).(referring to people such as Yanagisawa (1988), Nature 332:411-415) is a kind of 21 potent amino acid peptide vasoconstrictors to the endothelium peptide of finding in the culture supernatants of porcine aorta endotheliocyte.It is the most potent known vasopressor, and can be produced by many kinds of cells, comprising: endothelium, tracheae, kidney and brain cell.The endothelium peptide is 203 amino acid precursor anterior endotheliums of synthetic peptide former (preproendothelin), wherein contains a signal sequence, can be cracked into 38 (mankind) or 39 (pig) amino acid peptides by endogenous protease.This intermediate is called big endothelium peptide, in in vivo changing into sophisticated biological activity type through a kind of endothelin-converting enzyme of guessing (ECE), this saccharase appears as a kind of neutral protease that relies on metal (referring to for example: people such as Kashiwabara (1989) EEBS Lttrs.247:337-340).Splitting action is necessary (referring to for example: people (1991) such as Von Geldern, Peptide Res.4:32-35) to inducing physiological response.In the porcine aorta endotheliocyte, these 39 amino acid intermediates (big endothelium peptide) are in Trp 21-Val 22The key hydrolysis produces endothelium peptide-1 and C-terminal fragment.In the human cell, similar splitting action also takes place in 38 amino acid intermediates.Identified three kinds and had the active different endothelium peptides of potent vasoconstrictor, be i.e. endothelium peptide-1, endothelium peptide-2 and endothelium peptide-3 with the merit peptide.
These three kinds with merit peptide family: endothelium peptide-1, endothelium peptide-2 and endothelium peptide-the 3rd, by three kinds of gene clusters codings (referring to, people such as Inoue (1989), Proc.Natl.Acad.Sci.USA, 86:2863-2867; Also referring to people such as Saida (1989), J.Biol.Chem.264:14613-14616).The nucleotides sequence of three-type-person's genoid is listed in the regional inner height of 21 amino acid peptides of encoding mature and guards, and the C-terminal portions of peptide is all identical.Endothelium peptide-2 is (Trp 6, Leu 7) endothelium peptide-1, and endothelium peptide-3 is (Thr 2, Phe 4, Thr 5, Tyr 6, Lys 7, Tyr 14) endothelium peptide-1.So terminal high conservative of the C-of these peptides.Stimulated by many chemical and physical property by the effect that in endothelial cells cultured, discharges the endothelium peptide and regulate, and as if transcribing and/or the translating phase adjusting.Chemical stimulation comprises suprarenin, zymoplasm and Ca 2+Ionophore can improve the expression of gene of coding endothelium peptide-1.By endothelium produce and the effect that discharges the endothelium peptide then be subjected to angiotonin II, vasopressing, intracellular toxin, S-Neoral and other stimulate in the factor (referring to people such as Brooks (1991), Eur.J.Pharm, 194:115-117), and oxidated nitrogen suppresses.As if endotheliocyte can secrete short-life relaxation factor derived from endothelium (EDRF) when stimulated by vasoactive agent such as vagusstoff and bradykinin, comprise nitrogen oxide or related substances (people (1987) such as Palmer, Nature, 327:524-526).Be subjected to vasoconstriction effect that the endothelium peptide brings out also owing to anterior chamber's natriuretic peptide (ANP) weakens.
The endothelium peptide in vivo all has many biological activitys external reaching.The endothelium peptide causes strong and lasting vasoconstriction effect in the vascular smooth muscle preparation that mouse in vivo and separates; It also causes by discharging quasi-eicosane alcohol (eicosanoids) in the vescular bed of lavation and derived from the relaxation factor (EDRF) of endothelium.Through intravenous administration endothelium peptide-1 and external interpolation endothelium peptide-1 to blood vessel and other smooth muscle tissues, can produce respectively long lasting pressurization and contraction (referring to for example: people such as Bolger, Can.J.Physiol, Pharmacol, 69:406-413).For example in isolating vascular strip, endothelium peptide-1 is potent (EC 50=4 * 10 -10M), the slow but lasting shrinking agent of effect.In vivo, single dose was at about 20 to the 30 minutes blood pressures that can raise.The vasoconstriction effect that the endothelium peptide is brought out is not influenced by the antagonist of the known neurotransmitter or the hormone factor, but suppressed by calcium-channel antagonists.Yet the influence of calcium-channel antagonists most possibly is to suppress the result that calcium current is gone into effect, this be because calcium current to go into effect seemingly essential to the long-lasting contractile response of endothelium peptide.
The endothelium peptide is also regulated feritin and is discharged, stimulates ANP to discharge and bring out the enhancing contraction in the cavy anterior chamber.In lung, endothelium peptide-1 act as potent bronchoconstriction agent (people (1989) such as Maggi, Eur.J.Pharmacol., 160:179-182).The endothelium peptide improves kidney blood vessel resistance, lowers the kidney blood flow, and reduces Glomerular filtrate speed.It is the potent mitotic factor of mesangial cell, and the reaction of these cell moderate stimulation inosinyl phosphate inosine stepwises (people (1990) such as Simonson, J.Clin.Invest., 85:790-797).
In vascular system and the hetero-organization thereof (comprising intestines, heart, lung, kidney, spleen, suprarenal gland and brain), the specificity high-affinity binding site of endothelium peptide is all arranged, and (dissociation constant is in 2-6 * 10 -10In the scope of M).Keying action is not suppressed by catecholamine, vasoactive peptide, neurotoxin or calcium-channel antagonists.The endothelium peptide can combine with the acceptor site that is different from other autonomy acceptors and voltage-dependent ca channel and interact.Find have several receptoroids that the endothelium peptide is had different affinities with the merit peptide by CBA.Sha Luofu toxicity (sarafotoxin) is a kind of peptide toxin from snake Atractaspis eingadensis venom, it can make by snakebite person and serious coronary artery spasm occur, its 26S Proteasome Structure and Function is a homology with endothelium peptide-1 all, and can with the competition of identical heart membrane receptor in conjunction with (people (1989) such as Kloog, Trends Pharmacol.Sci., 10:212-214).
Identify two kinds of different endothelium peptide acceptors, be called ET AAnd ET B, and isolate dna clone (people (1990) such as Arai, Nature, the 348:730-732 of each acceptor of coding; People such as Sakurai (1990), Nature, 348:732-735).As if the proteinic aminoacid sequence coded according to this DNA that clones, each acceptor contain 7 films apart from the district, and are similar to the membrane protein of G protein coupling on the structure.On many different tissues, (heart, lung, kidney and brain have been comprised) and have detected the messenger RNA(mRNA) of these two kinds of acceptors of coding.Receptor subtype be distributed as tissue specificity (people (1989) such as Martin, Biochm.Biophys.Res.Commun., 162:130-137).ET AAs if acceptor have selectivity to endothelium peptide-1, and mainly appear in the cardiovascular organization.ET BAcceptor mainly appears in the non-cardiovascular tissue, comprises central nervous system and kidney, and with three kinds of endothelium peptides with merit peptide interaction (people (1990) such as Sakurai, Natrure 348:732-734).In addition, appear at ET on the vascular smooth muscle AAcceptor is relevant with vasoconstriction, and relevant with cardiovascular, kidney and central nervous system disease; And be positioned at the ET of blood vessel endothelium BAcceptor is then relevant with vasorelaxation, and (people (1991) such as Takayanagi, FEBS Lttrs. 282:103-106), and become relevant with the bronchoconstriction venereal disease.
Because the distribution of acceptor kenel and each receptor subtype are to each affinity difference with the merit peptide, the endothelium peptide also changes with tissue is different with the activity of merit peptide.For example, endothelium peptide-1 suppresses in cardiovascular organization 125Endothelium peptide-1 keying action of I mark is than 40 to 700 times of endothelium peptides-the last 3.In endothelium peptide-1 and endothelium peptide-3 pair non-cardiovascular tissue such as kidney, suprarenal gland and the cerebellum 125The inhibition degree of endothelium peptide-1 keying action of I mark is then identical, and this represents ET AAcceptor mainly appears in the cardiovascular organization, and ET BAcceptor mainly appears in the non-cardiovascular tissue.
Some morbid state can improve endothelium peptide plasma concentration (referring to for example: No. the 5th, 382,569, international pct application WO94/27979 and United States Patent (USP), these documents are incorporated this paper into as a reference fully).Endothelium peptide-1 plasma concentration that is recorded in the healthy human body by radio immunoassay (RIA) is 0.26-5pg/ml.In shock, myocardial infarction, blood vessel convulsion curved property angina, renal failure and various different reticular tissue pathology, the concentration of endothelium peptide-1 and precursor thereof in the blood (big endothelium peptide) can improve.The patient who carries out hemodialysis or renal transplantation or suffer from cardiogenic shock, myocardial infarction or pulmonary hypertension once occurred up to 35pg/ml concentration (referring to people such as Stewart (1991), Annals Internal Med., 114:464-469).Because the endothelium peptide may be for locality but not the general regulatory factor, so endothelium/unstriated muscle endothelium peptide concentration at the interface may be far above circulation composition.
The patient who suffers from ischemic heart disease also can record the endothelium peptide concentration and improve (people (1990) such as Yasuda, Amer.Heart J., 119:801-806; People such as Ray (1992), Br.Heart J., 67:383-386).Late arterial sclerosis patient's circulation with organize endothelium peptide immunoreactivity increase more than 2 times (people (1991) such as Lerman, New Engl.J.Med., 325:997-1001).Endothelium peptide immunoreactivity also improves and thromboangiitis obliterans (Buerger ' s disease) (people (1990) such as Kanno, J.Amer.Med.Assoc., 264:2868) and the Raynaud's phenomenon ((people (1990) such as Zamora of Raynaud ' sphenomenon), Lancet 336, and is 1144-1147) relevant.Acceptance penetrates patient (people (1991) such as Tahara, Metab.Clin.Exp., the 40:1235-1237 of the coronary angioplasty (PTCA) of tube chamber through the skin formula; People such as Sanjay (1991), 726), and the patient of pulmonary hypertension (people (1992) such as Miyauchi, Jpn.J.Pharmacol.58:279P Circulation84 (supplementary copy 4):; People such as Stewart (1991), Ann.Internal Medicine 114:464-469), the phenomenon that the circulation endothelium peptide concentration increases also occurs.Therefore, have clinical human trial data support the endothelium peptide concentration to improve and many kinds of diseases between dependency.Endothelium peptide agonists and antagonist
Because the endothelium peptide is relevant with some disease and relate to many kinds of physiological actions, the compound that therefore can disturb or strengthen endothelium peptide related activity (as endothelium peptide-acceptor interaction and vasoconstrictor activity) promptly merits attention.Now identified compound with endothelium peptide antagonistic activity.For example: the tunning (being called BE-18257B) of three rugged streptomycetes (Streptomyces misakiensis) has been accredited as ET AReceptor antagonist.BE-18257B is a kind of ring pentapeptide, ring (D-Glu-L-Ala-allo-D-Ile-L-Leu-D-Trp), and its concentration dependent ground in cardiovascular organization suppresses 125Endothelium peptide-1 keying action (the IC in aortal smooth muscle of I mark 50Being 1.4 μ M, is 0.8 μ M in the film of chamber, and is 0.5 μ M in the aortic smooth muscle cell through cultivating), but at ET BAcceptor density reaches in the tissue of 100 μ M, then can't suppress the keying action with acceptor.The now synthetic ring pentapeptide relevant with BE-18257B as ring (D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123), and shown to have as ET AThe activity of receptor antagonist (referring to United States Patent (USP) the 5th, 114, No. 918 (people such as Ishikawa); Also referring to EPA 10 436 189 (BANYUPHARMACUTICAL CO., LTD.1991 October 7).Measure these cyclic peptide suppress endothelium peptides-1 and endothelium peptide specificity acceptor keying action studies show that the preferential and ET of these cyclic peptide AReceptors bind.Now identified the ET of other peptides and non-peptide AAntagonist (referring to for example: the 5th, 352,800,5,334,598,5,352,659,5,248,807,5,240,910,5,198,548,5,187,195,5,082, No. 838 United States Patent (USP)s).These antagonists comprise other ring pentapeptides, acyl group tripeptides, six peptide analogs, some anthraquinone derivative, indane carboxylic acid (indanecarboxylic acids), some N-pyrimidyl benzsulfamide, some benzsulfamide and some naphthalene sulfonylamide (people such as Nakajima, (1991), J.Antibiot.44:1348-1356; People such as Miyata (1992), J.Antibiot.45:74-8; People such as Ishikawa (1992), J.Med.Chem.35:2139-2142; The 5th, 114, No. 918 United States Patent (USP)s of people such as Ishikawa; EP A 10,569 193; EP A 10,558 258; EP A10436 189 gives BANYU PHARMACEUTICAL CO., LTD (on October 7th, 1991); Canadian patent application 2,067,288; Canadian patent application 2,071,193; United States Patent (USP) 5,208,243; United States Patent (USP) 5,270,313; United States Patent (USP) 5,612,359; United States Patent (USP) 5,514,696; United States Patent (USP) 5,378,715; People such as Cody (1993) Med.Chem.Res.3:154-162; People such as Miyata (1992) J.Antibiot 45:1041-1046; People such as Miyata (1992), J.Antibiot 45:1029-1040; People such as Fujimoto (1992) FEBS Lett.305:41-44; People such as Oshashi (1002) J.Antibiot 45:1684-1685; EP A10496 452; People such as Clozel (1993) Nature 365:759-761; International Patent Application WO 93/08799; People such as Nishikibe (1993) Life Sci.52:717-724; And people (1993) Kidney Int.44:440-444 such as Benigni).The 5th, 464,853,5,594,021,5,591,761,5,571,821,5,514, in No. 691 United States Patent (USP)s, No. the 96/31492nd, international pct application and the international pct application WO97/27979 number many sulphonamide of endothelin antagonists that are have been described also.
Usually, compounds identified has ET under about 50-100 μ M or lower concentration in vitro test AAntagonistic activity.Many these compounds also have activity in the animal model in vivo.With endothelin antagonists and agonist as therapeutical agent
Known in the standard body outer analysis method of test endothelin antagonists or agonist activity, in IC 50Or EC 50Be 10 -4Or have active compound under the lower concentration and have pharmacology and use (referring to for example United States Patent (USP) 5,352,800,5,334,598,5,352,659,5,248,807,5,240,910,5,198,548,5,187,195 and 5,082,838).Because this activity thinks that these compounds are applicable to that treatment hypertension such as periphery circulate bad, heart trouble such as stenocardia, myocardosis, arteriosclerosis, myocardial infarction, pulmonary hypertension, vasospasm, vascular restenosis, raynaud's disease, cerebral apoplexy such as cerebral arteries convulsion are curved, cerebral ischemia, later stage brain spasm behind many spiders film bleed bottom, asthma, bronchoconstriction, renal failure, renal failure behind the ischemic particularly, S-Neoral renal toxicity such as acute renal failure, colitis, and other inflammation, because of the endothelium peptide causes or the endotoxin shock relevant with the endothelium peptide, and other relate to the disease of endothelium peptide.
With regard to many physiological actions of endothelium peptide and with regard to the dependency of some disease, tool letter endothelium peptide is played an important role in these pathologic, physiologic illnesss (referring to for example: people such as Saito (1990) Hypertension 15:734-738; People such as Tomita (1989) N.Engl.J.Med.321:1127; People such as Kurihara (1989) J.Cardiovasc.Pharmacol.13 (Suppl.5): S13-S17; Doherty (1992) J.Med.Chem.35:1493-1508; People such as Morel (1989) Eur.J.Pharmacol.167:427-428).If the function of endothelium peptide family peptide and the more detailed knowledge of configuration aspects can be provided, can understand the development and the therapeutics of these illnesss.
Regulated or the pathology relevant by the endothelium peptide in order helping further to understand and study, to need to differentiate and to adjust or to change the active compound of endothelium peptide with the endothelium peptide.Discriminating can be adjusted the active compound of endothelium peptide, has the compound of specificity antagonist or agonist effect as those, may not only help to illustrate the function of endothelium peptide, but also can produce medicative compound.Particularly, but specificity is disturbed endothelium peptide and ET AOr ET BThe compound of acceptor interaction should can be used for differentiating the necessary characteristic of endothelium peptide, should help to design medicine, and is available as the specificity medicine of disease.As mentioned above, chemical compound lot, particularly sulfonamide compounds are potent endothelin antagonists, and are the clinical candidates of ideal therefore.When clinical use, need potent compound and the stable composition and the composition that is applicable to various administrations of activity in vivo the best.
Therefore, the purpose of this invention is to provide to have and adjust the compound of one or more endothelium peptides in the body with the biological activity ability of merit peptide.Another purpose provides the compound as specificity endothelin antagonists in the body.Another purpose be can with ET AThe acceptor specificity interacts or suppresses endothelium peptide and ET AThe purposes of the interactional compound of acceptor specificity.Another purpose provides these compound compositions that are used for the treatment of the disease that is subjected to the adjusting of endothelium peptide.These compounds should be available as treatment and be subjected to the disease of endothelium peptide adjusting and the medicine that disease becomes.
Brief summary of the invention
The invention provides and adjust endothelium peptide and ET AAnd/or ET BThe sulphonamide of acceptor interaction, the composition of sulphonamide and method.Particularly, provide inhibition endothelium peptide and ET AOr ET BThe sulphonamide of receptors bind effect, the composition of sulphonamide and method.This sulphonamide is thienyl, furyl, pyrryl and the phenyl-sulfamide that is substituted or is unsubstituted.
Particularly preferred sulphonamide is N-isoxazolyl thiophenesulfonamide, furyl, pyrryl and phenyl-sulfamide, and wherein thiophene, furans, pyrroles or phenyl ring are replaced by aryl, preferred phenyl, and it has only one or two hydrogen substituting group.Have two substituent compounds of above hydrogen with aryl wherein and compare, described compound has transformation period and/or stability in better effectiveness, effectiveness, bioavailability, the body, and has avoided the toxic action relevant with hydrophobicity simultaneously.In addition, as if these compounds have good curve in the toxotest outside standard body.
When finding administration in vivo, wish that sulphonamide reaches the wetting ability of suitable degree, this can reduce compound potential hemolytic.If for example the aryl of substituted thiophene, furans, pyrroles or phenyl ring is four, five or hexabasic, preferred four or five replacements, then can realize this target.If aryl is quaternary, preferably 1,2,4 and 6 replacement.1 substituting group is connected with thiophene, furans, pyrroles or phenyl ring.2,4 or one of the substituting group at position place preferably polar group, for example hydroxyl, acetoxyl group, carboxyl, alkylsulfonyl, acyl group, heteroaryl, oxime, halogen, pseudohalogen and carboxylic acid amides (carboxamide).These replacements can strengthen the endothelin antagonists activity and the wetting ability of compound.
If aryl is replaced by 3 non-polar groups, as alkyl, more specifically be methyl, then aryl be preferably five-or hexabasic.In described five aryl that replace; when the 4th substituting group is connected thiophene, furans, pyrroles or phenyl ring; and the 5th substituting group polar group preferably, as hydroxyl, acetoxyl group, carboxyl, alkylsulfonyl, acyl group, heteroaryl, oxime, halogen, pseudohalogen and carboxylic acid amides.For realizing the activity of highest level in the treatment application, these replacements are preferred.
These replacements make compound have the interior transformation period of body of good bioavailability, length and/or the good interior effectiveness of body.With regard to said, use suitable animal model also can determine other so suitable substitute mode and substituting group empirically.
Used compound is the sulfonamide compounds with following general formula I in composition of the present invention and the method:
Ar 2-SO 2-NH-Ar 1(I) acceptable derivates, wherein Ar and on the pharmacology 1Be aryl or the heteroaryl that does not replace or replaced by one or more substituting group, described substituting group comprises alkyl, aryl, substituted aryl, nitro, amino or halogen; Or alkyl.Particularly, Ar 1Be that alkyl or 5 or 6 yuan replace or not substituted aroma or assorted aromatic nucleus, particularly 3-or 5-isoxazolyl pyridazinyl, pyrazinyl, comprise the 2-pyrazinyl, thiazolyl comprises the 2-thiazolyl, the diazosulfide base, comprise 2,1,3-diazosulfide-5-base, benzo oxadiazoles base comprises 2,1,3-benzo oxadiazoles-5-base, pyrimidyl comprises the 2-pyrimidyl, or substituted-phenyl, comprise the aryloxy substituted-phenyl, or two rings or three ring carbon or heterocycles.
For Ar 1Preferred group is 3-or 5-isoxazolyl.In these embodiments, compound has with Formula Il:
Figure A0081806100351
R wherein 1And R 2Be following (i), (ii) or (iii):
(i) R 1And R 2Be independently selected from respectively in H, NH 2, NO 2Halogen; pseudohalogen; alkyl; alkenyl; alkynyl group; aryl; aralkyl; heteroaryl; alkoxyl group; alkylamino; alkylthio; alkyl oxy; haloalkyl; the alkyl sulfinyl; alkyl sulphonyl; aryloxy; arylamino; arylthio; the aryl sulfinyl; aryl sulfonyl; haloalkyl; halogenated aryl; carbalkoxy; alkyl-carbonyl; aminocarboxyl; aryl carbonyl; formyl radical; replace or the sunsubstituting formyl amine base; and replace or do not replace urea groups; alkyl wherein; alkenyl and alkynyl group partly comprise 1-14 carbon atom; and can be straight or branched or cyclic; and aryl moiety comprises 4-16 carbon atom, but R 2Not halogen or pseudohalogen; Perhaps
(ii) R 1And R 2Formation-(CH together 2) n-, wherein n is 3-6; Perhaps
(iii) R 1And R 2Form the 1,3-butadiene base together (CH=CH-CH=CH-).
In preferred embodiments, R 1And R 2Be independently selected from respectively in alkyl, low-grade alkenyl, alkynyl of low-grade chain, low-grade halogenated alkyl, halogen, pseudohalogen or H, but R 2It or not halogen.
In the compound that is used for composition of the present invention and method, Ar 2Be thienyl, furyl, pyrryl or the phenyl that has with following formula: Wherein M is-C (Y)-W-, (CH 2) mC (Y) (CH 2) r, (CH 2) mC (Y) NH (CH 2) r, (CH 2) m(CH=CH) (CH 2) r, (CH 2) mC (Y) (CH 2) sNH (CH 2) r, C=N (OH) (CH 2) r, (CH 2) mC (Y) (CH=CH) sNH (CH 2) r, CH (OH) (CH 2) r, CH (CH 3) C (Y) (CH 2) r, CH (CH 3) C (Y) (CH 2) m(CH=CH) (CH 2) r, (CH 2) r, (CH 2) rO or (CH 2) S (O) nWherein n is 0-2; M, s and r are 0-6 respectively independently, are preferably 0-3; W is O, NH or (CH 2) z, wherein z is 0-6, is preferably 0-3, more preferably 1; And Y is O, S, perhaps with R 8And the atom that they connected forms 3-16 unit not replacement or substituted ring or heterocycle together, is preferably 5 or 6 yuan of not replacement or substituted ring or heterocycles, and more preferably 6 yuan do not replace or substituted heterocycle; M preferably-C (Y)-W-or (CH 2) z
R 3And R 4Be independently selected from hydrogen, halogen, cyano group, cyano group alkyl, C (O) R 41, alkyl, alkenyl, cycloalkyl and aryl, or form alkylidene group or alkenylene, wherein R together 41Be alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkyl amido, arylamino, ammonia diaryl base, alkyl sulfonyl-amino, arlysulfonylamino, alkyl sulphonyl alkylamino, alkyl sulphonyl arylamino, aryl sulfonyl alkylamino or aryl sulfonyl arylamino;
Y 1And Y 2Be respectively carbon or nitrogen independently; A and b are respectively 0 or 1 independently;
R 5, R 6, R 7, R 8And R 9Following independently respectively be selected from (i) or (ii):
(i) R 5, R 6, R 7, R 8And R 9Be independently selected from respectively in H, OH, NHR 38, CONR 38R 39, NO 2Cyano group; halogen; pseudohalogen; alkyl; alkenyl; alkynyl group; aryl; aralkyl; heteroaryl; alkoxyl group; alkylamino; alkylthio; haloalkyl; the alkyl sulfinyl; alkyl sulphonyl; carbalkoxy; alkyl-carbonyl; alkenyl thio; alkenyl amino; alkenyl oxy; the alkenyl sulfinyl; the alkenyl alkylsulfonyl; carbalkoxy; aromatic yl aminocarbonyl; alkylamino-carbonyl; aminocarboxyl; (alkyl-aminocarboxyl) alkyl; acetoxyl group; hydroxyl; carboxyl; carboxyalkyl; the carboxyl thiazolinyl; the alkyl sulfonyl-amino alkyl; the cyano group alkyl; ethanoyl; the acetoxyl group alkyl; hydroxyalkyl; the alkoxyl group alkoxyl group; hydroxyalkyl; (acetoxyl group) alkoxyl group; (hydroxyl) alkoxyl group; formyl radical; SULPHURYL CHLORIDE; amino acid; hexose; O-glycosides; ribose; low alkyl group; CN;-(CH 2) xC (O) (CH 2) yCH 3,-(CH 2) xCH 3, (CH 2) xThe NH-low alkyl group ,-(CH 2) xC (O) NH 2, D-, L-or DL-Amino Acid, uncle or secondary amide, O-glycosides, hexose or ribose ,-S (O) 2NH 2, hydroxyl, alkoxyl group, carbalkoxy, acetoxyl group alkyl ,-(CH 2) xCOOH ,-(CH 2) xCH (COOH) (CH 2) yCH 3, CO 2-low alkyl group, CN, heteroaryl, C (O) (CH 2) xS (O) 2(CH 2) yCH 3, C (=N-OR 38) (CH 2) yCH 3,-C (O) C (O) (CH 2) yCH 3,-(CH 2) xN (CH 3) 2, SULPHURYL CHLORIDE, S (O) 2NHR 50, OS (O) 2NR 38R 39, alkylaryl, miscellaneous alkyl aryl, C (O) NHR 50,-(CH 2) xOH and-C (O) N (H) N (H) R 50
R wherein 38And R 39Be independently selected from respectively in hydrogen, alkyl, alkenyl, alkynyl group, aryl, haloalkyl, alkylaryl, heterocyclic radical, aralkyl, alkoxy aryl, alkoxyl group, aryloxy, cycloalkyl, cycloalkenyl group and cycloalkynyl radical, and preferably be selected from hydrogen respectively, low alkyl group, lower alkoxy and low-grade halogenated alkyl; X and y are respectively 0-14 independently; And R 50It is substituting group such as hydrogen, low alkyl group, lower alkoxy or heteroaryl; Perhaps
The (ii) R of adjacent carbons on the substituted ring 5, R 6, R 7, R 8And R 9In at least two form alkylenedioxy group together, alkylidene group sulfo-oxygen base oxygen base or alkylidene group dithio oxygen base are (as-O-(CH 2) n-O-,-S-(CH 2) n-O-,-S-(CH 2) n-S-, wherein n is 1-4, is preferably 1 or 2), these groups be do not replace or one or more hydrogen atom by being substituted by halogen, low alkyl group, lower alkoxy or junior alkyl halides displacement, and other R 5, R 6, R 7, R 8And R 9Then as (i) selecting; And
X is-C (R 3)=C (R 4)-, S, O or NR 11, R wherein 11Be hydrogen or comprise at most about 30 carbon atoms, preferred 1-10 carbon atom, more preferably 1-6 carbon atom, and be selected from hydrogen, alkyl, alkenyl, alkynyl group, aryl, alkylaryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, C (O) R 15And S (O) nR 15, wherein n is 0-2; R 15Be hydrogen, alkyl, alkenyl, alkynyl group, aryl, alkylaryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group or cycloalkynyl radical; R 11And R 15Be not replace or replaced by one or more substituting groups that are independently selected from Z, described Z comprises hydrogen, halogen, pseudohalogen, alkyl, alkoxyl group, alkenyl, alkynyl group, aryl, amino acid, primary and secondary acid amides, O-glycosides, hexose, ribose, alkylaryl, miscellaneous alkyl aryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, OH, CN, C (O) R 16, OC (O) R 16, CO 2R 16, OCO 2R 16, SH, S (O) nR 16Wherein n is 0-2, NHOH, NR 12R 16, NO 2, N 3, OR 16, R 12NCOR 16And CONR 12R 16R 16Be hydrogen, alkyl, alkenyl, alkynyl group, aryl, alkylaryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, chlorine, NHR 50, alkylaryl, miscellaneous alkyl aryl or-(CH 2) xOH; R 50It is substituting group such as hydrogen, low alkyl group, lower alkoxy or heteroaryl; X is 0-14; R 12Be independently selected from R 11And Z, be selected from hydrogen, alkyl, alkenyl, alkynyl group, aryl, alkylaryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, C (O) R 17And S (O) nR 17N is 0-2 wherein; R 17Be hydrogen, alkyl, alkenyl, alkynyl group, aryl, alkylaryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group or cycloalkynyl radical; R 12And R 16Can form alkylidene group together; R 11, R 12, R 15And R 16Can distinguish further and be replaced by the proper group among the Z.
In all embodiments, X preferably S or-CH=CH-, be more preferably S.
In certain embodiments, the selection of compound has following precondition: R 5, R 6, R 7, R 8And R 9In have two to be hydrogen at most.In another embodiment, the selection of compound has following precondition: R 5, R 6, R 7, R 8And R 9In have one to be hydrogen at most.
In another embodiment, described compound has formula I or II, its precondition is: compound is not disclosed among international application published WO 94/27979, WO 96/31492, WO 98/13366 and the WO 98/49162 particularly, and the content of these documents is incorporated herein by reference at this.
In another embodiment, the selection of compound has following precondition: R 8Not COOH, CONH 2Perhaps phenyl.
In the compound as herein described, preferably those concentration below about 10 μ can suppress or improve the compound that the endothelium peptide is regulated activity about 50%.More preferably when the following concentration of 1 μ M, with below about 0.1 μ M more preferably, even below about 0.01 μ M more preferably, most preferably, can suppress or improve the endothelium peptide and regulate active about 50% compound below about 0.001 μ M.It should be noted that, as described below, in the IC of analyzed in vitro method mensuration 50Concentration is the nonlinear function of culture temperature.In this article, the analytical method that obtains preferred value is carried out under 4 ℃.When analytical method is carried out, can be observed the IC of high slightly (seeing Table 1) under 24 ℃ 50Concentration.Therefore, preferred IC 50High about 10 times of concentration.In addition, in these compounds, it is most preferred measuring the compound with maximum bioavailability and stability with standard animal model.
The most preferred compound that also is used for method that this paper provides is that those have ET ASelectivity person that is to say, far below with ET B(IC under the concentration of acceptor interaction 50At least low about 10 times, preferably low 100 times) and ET AAcceptor interaction.Particularly, preferably, with ET AInteractional IC 50Below about 10 μ M, preferably be lower than 1 μ M, more preferably less than 0.1 μ M, but and ET BIC 50The compound that about 10 μ M are above, or and ET BInteractional IC 50Below about 10 μ M, preferably be lower than 1 μ M, but and ET AIC 50Be the compound more than about 10 μ M.
The invention still further relates to acceptable derivates on any pharmacology of sulphonamide, comprise salt, ester, acid and alkali, solvate, hydrate and prodrug.Acceptable salt on the pharmacology preferably, include but not limited to amine salt, such as but not limited to N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkyl amine, quadrol, the N-methylglucosamine, PROCAINE HCL, PHARMA GRADE, the N-benzyl-1-phenylethylamine, 1-p-chlorobenzyl-2-tetramethyleneimine-1 '-Ji-tolimidazole, diethylamide and other alkylamine, piperazine, three (methylol) aminomethane, an alkali metal salt, such as but not limited to lithium, potassium and sodium, alkaline earth salt, such as but not limited to barium, calcium and magnesium, transition metal salt, such as but not limited to zinc, and other metal-salt, such as but not limited to sodium hydrogen phosphate and sodium phosphate, particular certain cancers, more preferably sodium salt, but also include but not limited to the salt of mineral acid, such as but not limited to hydrochloric acid and vitriol, organic acid salt is such as but not limited to acetate, lactic acid salt, malate, tartrate, Citrate trianion, ascorbate salt, succinate, butyrates, valerate and fumarate.At this preferred as alkali salt, particularly sodium salt, most preferred salt is sodium salt.
The present invention also is provided for the pharmaceutical composition through suitable approach and means administration, it contains acceptable salt on the pharmacology of one or more compounds that this paper provided of effective concentration or this sulphonamide, ester, bronsted lowry acids and bases bronsted lowry, solvate, hydrate and prodrug, preferably salt, more preferably sodium salt, include but not limited to sodium salt and sodium hydrogen phosphate salt, sodium salt most preferably, said composition discharges effective dose, be used for the treatment of hypertension, apoplexy, cardiovascular disorder, heart trouble comprises: myocardial infarction, pulmonary hypertension, new natural disposition pulmonary hypertension, the hypertension that erythropoietin is regulated, respiratory disease and inflammation comprise asthma, bronchoconstriction, eye disease comprises that glaucoma and retina perfusion are insufficient, gastrointestinal illness, renal failure, endotoxin shock, the menstruation disease, obstetrics' disease, injured, the plate inflammation, erective dysfunction, menopause, osteoporosis and bone metabolic disease, the weather disease comprises hot flush, unusual grumeleuse behavior, the sickness rate of urethra reproductive tract discomfort and cardiovascular disorder increases, with other and middle-aged women ovarian function decline diseases associated, preeclampsia, the control of gestation time, anaphylactic shock, hemorrhagic shock, the disease that nitrogen oxide weakens, and other relate to by the disease of the physiological response of endothelium peptide adjusting or relate to vasoconstrictive disease or administration endothelin antagonists or agonist can be alleviated the disease of its symptom.
Preparation of the present invention is the composition that is applicable to by any desirable administration, and it comprises the aerosol of solution, suspension, emulsion, tablet, dispersible tablet, pill, capsule, powder, inhalant dry powder, sustained release preparation, nasal cavity and respiratory tract administration, the medicine subsides of transdermal administration and the formulation of any other suitable pathways administration.The present composition should be applicable to the oral administration administration, non-through gi tract by drug administration by injection, this comprises with injection of aqueous solution or oil solution or emulsion through subcutaneous, intramuscular or intravenous injection, transdermal administration and other route of administration through selecting.
The present invention also provides lyophilized powder, its preparation method of sulfone amide derivative and the preparation that comprises the lyophilized powder of recovery form.The phial, ampoule, syringe and other suitable vessel that comprise powder also are provided.
Preferred formulation comprises acceptable salt on the pharmacology that contains sulphonamide, particular certain cancers, the more preferably aseptic freeze-dried powder of a sodium salt, also comprises capsule and tablet.Particularly preferred preparation is that those discharge the hypertension therapy of effective dose or the preparation of renal failure.Effective dose and concentration are meant the amount of any symptom of any disease of effective alleviation.
In one embodiment, preparation is one or more salt, preferably phosphoric acid hydrogen sodium salt or the sodium salt that comprise the sulfonamide compounds of one or more formulas I, the more preferably lyophilized solid of sodium salt, it also comprises following one or more materials: buffer reagent, as potassiumphosphate or sodium, Citrate trianion; Solubilizing agent, as LABRASOL (Gattefosse SA, polyoxyethylene glycol-8-octyl-decyl glyceryl ester that France sells), DMSO, two (trimethyl silyl) ethanamide, ethanol, propylene glycol (PG) or polyvinylpyrrolidone (PVP), and sugar or other carbohydrate, as sorbyl alcohol or glucose.
In other embodiments, preparation is a solid dosage, is preferably capsule or tablet.In preferred embodiments, preparation is a solid dosage, preferably capsule or tablet, it comprises 10-100 weight %, preferred 50-95 weight %, more preferably 75-85 weight %, one or more salt of one or more sulphonamide of the formula I of 80-85 weight % most preferably, preferably phosphoric acid hydrogen sodium salt or sodium salt, more preferably sodium salt; Vehicle or the tackiness agent of about 0-25%, preferred 8-15% are as lactose or Microcrystalline Cellulose; About 0-10%, the preferred disintegrating agent of about 3-7%, as treated starch or cellulose polymer compound, croscarmellose sodium particularly, (croscarmellose sodium NF can be from FMC Corporation as cross-linked carboxymethyl cellulose (crosscarmellose) sodium, Philadelphia, PA buys with the AC-DI-SOL trade(brand)name) or primojel; And the 0-2 lubricant, as Magnesium Stearate, talcum and calcium stearate.Can make after the dressing polymer dissolution fast the disintegration cellulose matrix with release of active agent immediately as the disintegrating agent of cross-linked cellulose sodium or primojel.In all embodiments, the accurate amount of activeconstituents and ancillary component can determine empirically, and relevant with the route of administration and the disease of being treated.
Be used for the solid dosage of administration such as tablet also within the scope of the invention.It should be understood that those skilled in the art can determine the accurate amount and the composition of described preparation empirically.
The present invention also provides and uses described preparation to adjust endothelium peptide and ET AAnd/or ET BThe interactional method of acceptor.This method is following realization: before making acceptor and the endothelium peptide contact, with its simultaneously or subsequently, make acceptable salt on one or more pharmacology of acceptor and sulphonamide, preferably the preparation of the sodium salt of sulphonamide contacts.
The present invention also provides the method that suppresses endothelium peptide and endothelium peptide receptors bind.The following realization of this method: before making acceptor and the endothelium peptide contact, with its simultaneously or subsequently, the preparation of acceptable salt on the pharmacology of acceptor and one or more The compounds of this invention or described compound is contacted.
The method of the treatment endothelium disease that peptide is regulated also is provided, described disease includes but not limited to: hypertension, asthma, shock, intraocular pressure are too high, glaucoma, the retina perfusion is insufficient and other are regulated according to some mode by the endothelium peptide illness, or are used for the treatment of and relate to the pathology that vasoconstriction maybe can be improved by administration endothelin antagonists or agonist.
Particularly, provide the method for treatment endothelin-mediated disorder, it is the sulphonamide of effective dosage, prodrug or other suitable derivatives of sulphonamide.Particular words it, provide the method for treatment endothelin-mediated disorder, comprise: hypertension, cardiovascular disorder, heart trouble comprises: myocardial infarction, pulmonary hypertension, new natural disposition pulmonary hypertension, the hypertension that erythropoietin is regulated, respiratory disease and inflammation, comprise asthma, bronchoconstriction, eye disease comprises that glaucoma and retina perfusion are insufficient, gastrointestinal illness, renal failure, endotoxin shock, the menstruation disease, obstetrics' disease, injured, the plate inflammation, erective dysfunction, menopause, osteoporosis and bone metabolic disease, the weather disease comprises hot flush, unusual grumeleuse behavior, the sickness rate of urethra reproductive tract discomfort and cardiovascular disorder increases, with other and middle-aged women ovarian function decline diseases associated, preeclampsia, the control of gestation time, the disease that nitrogen oxide weakens, anaphylactic shock, hemorrhagic shock, and other relate to the disease by the physiological response of endothelium peptide adjusting, and this method is to realize by the compound of the present invention of one or more in the acceptable carrier on pharmacology of effective dosage.Preferred methods of treatment is treatment hypertension and renal failure.
Preferred therapeutics for those wherein composition contain at least a compound, this compound is at IC 50Below about 10 μ M, below preferred about 5 μ M, more preferably from about below the 1 μ M, even more preferably from about below the 0.1 μ M, and most preferably below the 0.05 μ M, can suppress endothelium peptide-1 and ET AAcceptor interaction.Other preferred method for those wherein composition contain one or more ET AAlternative cpd or one or more ET BAcceptable salt on the pharmacology of alternative cpd.Use ET AThe method of alternative cpd is to be used for the treatment of as hypertensive disease, and uses ET BThe method of alternative cpd is to be used for the treatment of the disease that needs expansion bronchus as asthma.
When operating this method, it is the individuality that the symptom of one or more following diseases appears in the significant quantity composition administration that will contain the compound for the treatment of effective concentration, said composition is deployed into per os, intravenously, fixed point and local dispenser, described disease is a hypertension, cardiovascular disorder, heart trouble comprises: myocardial infarction, pulmonary hypertension, new natural disposition pulmonary hypertension, the hypertension that erythropoietin is regulated, respiratory disease and inflammation comprise asthma, bronchoconstriction, eye disease comprises that glaucoma and retina perfusion are insufficient, gastrointestinal illness, renal failure, the kidney vasoconstriction of immunosuppressor mediation, endotoxin shock, the menstruation disease, obstetrics' disease, injured, the plate inflammation, erective dysfunction, menopause, osteoporosis and bone metabolic disease, the weather disease comprises hot flush, unusual grumeleuse behavior, the sickness rate of urethra reproductive tract discomfort and cardiovascular disorder increases, with other and middle-aged women ovarian function decline diseases associated, preeclampsia, the control of gestation time, anaphylactic shock, hemorrhagic shock, the disease that nitrogen oxide weakens, and other relate to the disease of the physiological response that the endothelium peptide regulated.Its consumption is for effectively improving or eliminate one or more symptoms of these diseases.
The present invention also provides the method for differentiating and separating endothelium peptide receptor subtype.Particularly, the compound that use is provided is disclosed with detect, differentiate, and the method for separating endothelium peptide acceptor.Particular words it, provide and use compound that this paper provides to detect, to differentiate and the method for separation endothelium peptide acceptor.
In addition, also provide evaluation to be applicable to the compound of treatment specified disease according to its selective affinity to specific endothelium peptide receptor subtype.
And provide the finished product that contain following material: wrapping material, be included in this paper in these wrapping material and provide and effectively to improve endothelin-mediated disorder and the IC below about 10 μ M 50But antagonism endothelium peptide effect or suppress endothelium peptide and the keying action of ET acceptor compound, and this compound of explanation or its pharmacology on acceptable salt be used for the label of the keying action of antagonism endothelium peptide effect, treatment endothelin-mediated disorder or inhibition skin peptide and ET acceptor.
The description of preferred embodimentDefinition
Unless otherwise defined, otherwise the scientific and technological noun that this paper adopted all with the same meaning of the common understanding of those skilled in the art.All patents and document that this paper mentions all are incorporated herein by reference at this.
The endothelium peptide (ET) that this paper adopted comprise have endothelium peptide-1 in fact, the aminoacid sequence of endothelium peptide-2 or endothelium peptide-3 and as the peptide of potent endogenous vasoconstrictor peptide effect.
" illness that the endothelium peptide is regulated " that this paper adopted is meant because of the active illness that maybe can adopt the active compounds for treating of inhibition endothelium peptide unusually of endothelium peptide.These diseases include but not limited to: hypertension, cardiovascular disorder, asthma, inflammation, eye disease, the change of menstruation venereal disease, obstetrics' illness, gastrointestinal illness, renal failure, pulmonary hypertension, endotoxin shock, anaphylactic shock or hemorrhagic shock.The illness that the endothelium peptide is regulated also comprises uses the illness that pharmaceutical treatment caused that improves the endothelium peptide concentration as meetings such as erythropoietin and immunosuppressor.
This paper adopts " the significant quantity compound that is used for the treatment of specified disease " for being enough to improve and reduce according to some mode the consumption of the symptom relevant with disease.These consumptions can single doses or can be according to effective administrations course of treatment.This consumption can be treated disease, but typically administration to improve the symptom of disease.Typically, need repeat administration, to reach the required symptom effect of improving.
It is a kind of bioactive compound relevant with the endothelium peptide or that had for the endothelium peptide of strengthening or have that this paper adopts " endothelium peptide agonists ".
This paper adopts " endothelin antagonists " for a kind of compound as medicine and antibody, can suppress the physiological response that vasoconstriction that the endothelium peptide stimulated and contraction and other endothelium peptides are regulated.The effect of antagonist can be disturbed the interaction of endothelium peptide and endothelium peptide specificity acceptor or disturb physiological response or the biological activity of endothelium peptide with the merit peptide, as vasoconstriction.Therefore, according to analytical method well known to those skilled in the art, vasoconstriction or other reactions or interference endothelium peptide and endothelium peptide specificity acceptor such as ET that this paper adopts " endothelin antagonists " can disturb the endothelium peptide to be stimulated AThe interaction of acceptor.
The validity of potential agonist and antagonist can be used the method known to those skilled in the art test.For example, endothelium peptide agonists activity can utilize its vasoconstrictive ability that stimulates separated mouse chest aorta or portal vein link to identify (people (1989) " tissue selectivity of endothelium peptide " (Tissue selectivity of endothelin) Eur.J.Pharmacol.165:223-230 such as Borges).The endothelin antagonists activity can be used for analyzing by its vasoconstriction of disturbing the endothelium peptide to be brought out.Analysis example is shown in the embodiment part.As mentioned above, preferred IC 50Concentration range is for the analytical method reference, and wherein test compound is to cultivate down in 4 ℃ with the cell that contains the ET acceptor.Existing the indicating of analytical data that the culturing step that carries out under more unfavorable 24 ℃ is shown.Be understandable that for relatively, this isoconcentration is all high slightly than the concentration that records in 4 ℃ the time.
This paper adopts " bioavailability " to be meant uptake rate and degree.The method of determining bioavailability is known for those skilled in the art.For example, the bioavailability of any compound that the present invention describes all can followingly be determined empirically: described compound administration in animal, is taked blood sample then in time, and measure the haemoconcentration of compound.Transformation period (t in the body 1/2) be defined as the compound haemoconcentration and reduce half needed time.Estimation intravenously administrable area under a curve can be used for estimating the oral administration area under a curve, and produces the biological utilisation degrees of data.Referring to for example MiloGibal (1991), Biopharmaceutics and Pharmacology, the 4th edition (Lea andSediger).
" usefulness " that this paper adopted is meant the producible maximum effect of compound.Usefulness can be measured with method known to those skilled in the art.For example, can determine, be reflected in then in the platform of concentration-effect curves according to the character and the acceptor-effector system thereof of compound.Usefulness is meant the usefulness of measuring in the body in animal model.For example, usefulness can be measured by the pulmonary hypertension of hypoxia inducible in mouse in the body of The compounds of this invention.Referring to people (1995) such as for example DiCarlo, Am.J.Physiol.269:L690-L697.
" compound that has good behavior in the external or toxicity in vivo experiment of standard " that this paper adopted is meant with respect to this compound of known endothelin antagonists and shows higher tolerance.Particularly, as described herein, when suppressing P450 enzyme, particularly CP4502C9,2C19 and 3A4 enzyme, have higher IC 50The compound of value has good behavior in the in vitro toxicity experiment of standard.Realize in the acute anoxia model that in the body of standard mean pulmonary arterial pressure (MPAP) needs the compound of lower dosage to have behavior in the good body when increasing by 50% inhibition.
It is any in the activity of in vivo being brought out, strengthening or influenced by the endothelium peptide that this paper adopts " biological activity of endothelium peptide " to comprise.Also comprise with special receptor bonded ability and bring out functional response such as vasoconstrictive ability.It can utilize in vivo analytical method or analyzed in vitro method (as this paper person of exemplifying) analysis.Related activity includes but not limited to: vasoconstriction, vasorelaxation and bronchiectasis.For example, ET BAs if acceptor is expressed in the vascular endothelial cell, and can regulate vasodilation and other these reactions; And the narrow spectrum ET of endothelium peptide-1 AAcceptor then appears on the unstriated muscle, and relevant with vasoconstriction.Those skilled in the art are known to be used for measuring or to detect these active any analytical methods and all can be used to analyze this isoreactivity (referring to for example: people such as Spokes (1989) J.Cardiovasc.Pharmacol.13 (supplementary copy 5): S191-192; People such as Spinella (1991) Proc.Natl.Acad.Sci.USA 88:7443-7446; People such as Cardell (1991) Neurochem.Int.18:571-574; And the embodiment of this paper).
" IC that this paper adopts 50" be meant that in the analytical method of measuring these reactions the specific maximum reaction of test compound inhibition is as the endothelium peptide and organize the keying action of acceptor to reach consumption, concentration or dosage at 50% o'clock.
" EC that this paper adopts 50" be meant that the reaction that specific test compound brings out with dosage reaches dosage, concentration or the consumption that this specific test compound brings out, excites or strengthen the maximum performance of specific reaction at 50% o'clock.
" ET that this paper adopts AThe selectivity sulphonamide " be meant that this sulphonamide is to ET AThe IC of acceptor 50Comparison ET BThe IC of acceptor 50At least low about 10 times.
" ET that this paper adopts BThe selectivity sulphonamide " be meant that this sulphonamide is to ET BThe IC of acceptor 50Comparison ET AThe IC of acceptor 50At least low about 10 times.
This paper adopts " acceptable salt, ester, hydrate, solvate or other derivatives on the pharmacology of compound " to comprise that those skilled in the art use the currently known methods of these derivatization methods to prepare and the compound that produced can deliver medicine to animal or human's class and nontoxicity and tool pharmaceutical activity or be any salt, ester or other derivative of prodrug in fact.Acceptable salt includes but not limited to an alkali metal salt and alkaline earth salt on the pharmacology, includes but not limited to sodium salt, sylvite, lithium salts, calcium salt and magnesium salts; Transition metal salt is as zinc salt, mantoquita and aluminium salt; Polycation counterion salt, such as but not limited to the ammonium salt of ammonium salt and replacement, and organic amine salt, as hydroxyalkyl amine and alkylamine; The salt of mineral acid, such as but not limited to hydrochloride and vitriol, organic acid salt is such as but not limited to acetate, lactic acid salt, malate, tartrate, Citrate trianion, ascorbate salt, succinate, butyrates, valerate and fumarate.Also comprise corresponding ester at this.
This paper adopts " sodium salt " to be meant the salt of any sodium compound, and wherein counterion comprises Na +, and can comprise other ion, as HPO 4 2-Described " sodium salt " is meant that especially counterion is Na +Salt.
This paper adopts " therapeutics " to be meant any way that improves or advantageously change the symptom of illness, pathology or disease.Therapeutics also comprises any pharmaceutical use of composition herein, as becomes the purposes of contraceptive bian.
It is any because of the administration or the relevant state of an illness that alleviates with the administration present composition that this paper adopts " symptom of improving specific pathology by administration certain drug composition " to be meant, no matter temporary transient or permanent, lasting or cambic.
This paper adopts " pure in fact " to be meant that its homogeneity is enough to make standard method of analysis to record can detected impurity, these analytical methods for as: those skilled in the art are commonly used to detect thin layer chromatography (TLC), gel electrophoresis and the high performance liquid chromatography (HPLC) of these impurity, or its purity reaches and is enough to make the physics that also can not change material and the degree of chemical property (as enzymic activity and biological activity) of being further purified.The method of purification that can produce chemically pure in fact compound is well known by persons skilled in the art.Yet chemically pure in fact compound can be the mixture of steric isomer.In the case, be further purified the specific activity that may improve compound.
This paper adopts " biological activity " to be meant the physiological response that the activity in vivo vivid of compound or compound, composition or other mixtures are administered in vivo to be produced.Therefore, biological activity comprises the result of treatment and the pharmaceutical activity of these compounds, composition and mixture.
This paper adopts " stability of formulation increase " to be meant with assay well known by persons skilled in the art, for example high performance liquid chromatography, vapor-phase chromatography etc., the activeconstituents in the preparation after the said preparation preparation preset time the place per-cent apparently higher than other composition after preparation the identical time place activeconstituents per-cent.In the case, just claim previous composition to have the stability of increase with respect to a back composition.
This paper adopt " prodrug " for a kind of can metabolism when being administered in vivo or change into the compound of biology, medicine or the therapeutic activity type of compound.In order to make prodrug, need the modified medicaments active compound, make active compound to produce via metabolic process.During the design prodrug, can change the metabolic stability or the transport features of medicine, cover side reaction or toxicity, improve other characteristics or the character of medicine taste or change medicine.Because those skilled in the art have understood intravital pharmaco-kinetic processes and drug metabolism, therefore in case known a kind of pharmaceutical active compounds, the prodrug that can design this compound is (referring to for example: Nogrady (1985) " medicinal chemistry, biological discussion ", Oxford University Press, New York (Medicinal Chemistry A BiochemicalApproach), Oxford University Press, New York), 388-392 page or leaf).For example, succinyl-sulphur thiazole is the prodrug of 4-amino-N-(2-thiazolyl) benzsulfamide (sulphur thiazole), can change transport features.
This paper adopt " sour isostere " be meant a kind of under physiological pH remarkable Ionized group.Suitable sour isostere example comprises sulfo group, phosphoryl, alkane Herbicidal sulphonylamino formyl radical, tetrazyl, arylsulfonyl carbamyl or assorted arylsulfonyl carbamyl.
This paper adopts " halogen or halogenide " to be meant halogen atom; F, Cl, Br and I.
This paper adopts " false halogenide " to be similar to halid compound in fact for its performance.These compounds can use and handle (" X according to halid same way as -", wherein X is a halogen, as Cl or Br).False halogenide includes but not limited to prussiate, cyanate radical, thiocyanate radical, selenium cyanate radical and trinitride.
This paper adopts " haloalkyl " to be meant low alkyl group, and one or more hydrogen atoms are replaced by halogen in the base, and it includes but not limited to chloromethyl, trifluoromethyl, 1-chloro-2-fluoro ethyl, or the like.
This paper adopts " alkyl " to be meant aliphatic hydrocarbyl, and it is for preferably containing the straight or branched chain of about 1 to 12 carbon atom in the chain.Preferred alkyl is to contain the 1 straight or branched chain low alkyl group to about 6 carbon atoms in the chain." side chain " is illustrated in attached one or more low alkyl groups such as methyl, ethyl or propyl group on the linear alkyl chain.Alkyl can be unsubstituted or replace through one or more groups respectively, such as but not limited to halogen, carboxyl, formyl radical, sulfo group, sulfino, carbamyl, amino and imino-.Examples of alkyl comprises methyl, ethyl, propyl group, carboxyl methyl, carboxy ethyl, carboxyl propyl group, sulfino ethyl and sulfonic group ethyl.
" rudimentary " is to be used to illustrate contain about 6 or still less alkyl, alkenyl and the alkynyl group of carbon atom herein.Also be used for illustrating that ring contains 6 or the still less aryl or the heteroaryl of carbon atom.Low alkyl group, low-grade alkenyl and low-grade alkynyl are meant and contain the following carbochain of about 6 carbon.The preferred embodiment of compound that this paper provides comprises alkyl, the alkenyl or alkynyl part that contains low alkyl group, low-grade alkenyl and low-grade alkynyl part.
This paper adopts " alkenyl " to be meant to contain a carbon-to-carbon double bond and can be and contains about 2 aliphatic hydrocarbyls to the straight or branched chain of about 10 carbon atoms in the chain.Preferred thiazolinyl is to contain 2 to 4 carbon atoms in chain." side chain " is illustrated in attached one or more low alkyl groups or low-grade alkenyl on the linear alkenylene chain.Alkenyl can be unsubstituted or replace through one or more groups respectively, as halogen, carboxyl, formyl radical, sulfo group, sulfino, carbamyl, amino and imino-.The alkenyl example comprises vinyl, propenyl, carboxyl vinyl, carboxylic propenyl, sulfino vinyl and sulfo group vinyl.
This paper adopts " alkynyl group " to be meant to contain a carbon-to-carbon triple bond and can be the aliphatic hydrocarbyl of the straight or branched chain that contains about 2 to 10 carbon atoms in the chain." side chain " is illustrated in attached one or more low alkyl groups, alkenyl or alkynyl on the linear alkynyl chain.The alkynyl group example is an ethynyl.
This paper adopts " aryl " to be meant to contain 3 to 15 or 16, the aromaticity monocycle or the polynuclear hydrocarbon ring system of preferred 5 to 10 carbon atoms.Aryl includes but not limited to phenyl, the phenyl that is substituted, naphthyl, the naphthyl that is substituted, and wherein substituting group is low alkyl group, halogen or lower alkoxy.Preferred aryl groups is to contain the following lower aryl of 7 carbon in the ring structure.
The nomenclature of alkyl that this paper adopts, alkoxyl group, carbonyl etc. is the usage that those skilled in the art understand.For example, this paper adopts " alkyl " to be meant the saturated carbon chains that contains one or more carbon; This chain can be straight or branched, or comprises circular part or can be ring-type.This paper adopts " alicyclic ring " to be meant the cyclic aryl.
This paper adopts " cycloalkyl " to be meant the saturated cyclic carbochain; " cycloalkenyl group " is meant the ring-type carbochain that comprises at least one unsaturated double bond or ginseng key respectively with " cycloalkynyl radical ".The circular part of carbochain can comprise a ring or two or more fused rings.
This paper adopts " cycloalkenyl group " to be meant to contain the non-aromaticity monocycle or the polycyclic system of a carbon-to-carbon double bond and about 3 to 10 carbon atoms.Monocyclic cycloalkenyl group example comprises cyclopentenyl or cyclohexenyl; Be preferably cyclohexenyl.The example of polycyclic system cycloalkenyl group is a norbornene.Cycloalkenyl group can replace through one or more halogens or alkyl respectively.
This paper adopts " haloalkyl " to be meant low alkyl group, and wherein one or more hydrogen atoms are replaced by halogen, and it includes but not limited to chloromethyl, trifluoromethyl, 1-chloro-2-fluoro ethyl, or the like.
This paper adopts " halogenated alkoxy " to be meant that wherein R is the RO-of alkylhalide group.
This paper adopts " carboxylic acid amides " to be meant suc as formula R pCONH 2Group, wherein R is selected from alkyl or aryl, is preferably low alkyl group or lower aryl, and p is 0 or 1.
This paper adopts " alkyl amino-carbonyl " to be meant-C (O) NHR that wherein R is hydrogen, alkyl, is preferably low alkyl group, or aryl, is preferably lower aryl.
This paper adopts " dialkyl amino carbonyl " to be meant-C (O) NR ' R that wherein R ' is selected from alkyl or aryl respectively with R, is preferably low alkyl group or lower aryl; This paper adopts " carboxylic acid amides " to be meant group suc as formula NR ' COR.
This paper adopts " carbalkoxy " to be meant-C (O) OR that wherein R is an alkyl, is preferably low alkyl group, or aryl, is preferably lower aryl.
This paper adopts " alkoxyl group " and " thioalkoxy group " to be meant RO-and RS-, and wherein R is an alkyl, is preferably low alkyl group, or aryl, is preferably lower aryl.
This paper adopts " halogenated alkoxy " to be meant that wherein R is the RO-of alkylhalide group.
This paper adopts " aminocarboxyl " to be meant-C (O) NH 2
This paper adopts " alkylamino radical carbonyl " to be meant-C (O) NHR, and wherein R is an alkyl, is preferably low alkyl group, or aryl, is preferably lower aryl.
This paper adopts " carbalkoxy " to be meant-C (O) OR that wherein R is an alkyl, is preferably low alkyl group.
This paper adopts " cycloalkyl " to be meant the saturated cyclic carbochain; Cycloalkenyl group and cycloalkynyl radical are meant the ring-type carbochain that comprises at least one unsaturated ginseng key.The circular part of this carbochain can comprise a ring or two or more fused rings.
This paper adopts " alkylenedioxy group " to be meant-O-alkyl-O-group that wherein moieties as mentioned above.The displacement analogue of alkylenedioxy group is meant in the alkylenedioxy group that one or two Sauerstoffatoms are showed the group of similar atom or atom such as S, N, NH, Se displacement.Metathetical alkylenedioxy group example is ethylenebis (sulfane two bases).Alkylene sulfenyl oxygen is-S-alkyl-O-,-O-alkyl-S-, and the alkylidene group disulfide group is-S-alkyl-S-.
This paper adopts " heteroaryl " to be meant the aromaticity monocycle or condenses one or more carbon atoms in the ring system by for example nitrogen, oxygen or sulphur displacement of the element beyond the carbon.Preferred cyclic group contains one or two fused rings, and each ring is 3 to about 7 yuan of rings.Heteroaryl is similar to " aryl ", can be unsubstituted or replaces through one or more substituting groups.The heteroaryl example comprises pyrazinyl, pyrazolyl, tetrazyl, furyl, (2-or 3-) thienyl, (2-, 3-or 4-) pyridyl, imidazolyl, pyrimidyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indyl, isoquinolyl, oxazolyl and 2,1,3-oxadiazoles base.Preferred heteroaryl comprises that 5 to 6 yuan contain azo-cycle, as pyrimidyl.
This paper adopts " carbalkoxy " to be meant alkyl-O-CO-group.The carbalkoxy example comprises methoxycarbonyl and ethoxy carbonyl.
This paper adopts " carbamyl " to be meant-CONH 2As all groups as herein described, these groups can be unsubstituted or be substituted.The carbamyl that is substituted comprises as CONY 2Y 3Group, wherein Y 2With Y 3Be respectively hydrogen, alkyl, cyano group (low alkyl group), aralkyl, heteroaralkyl, carboxyl (low alkyl group), carboxyl (low alkyl group that aryl replaces), carboxyl (low alkyl group of carboxyl substituted), carboxyl (low alkyl group that hydroxyl replaces), carboxyl (low alkyl group that heteroaryl replaces), carbamyl (low alkyl group), carbalkoxy (low alkyl group) or carbalkoxy (low alkyl group that aryl replaces), but its restricted condition is: Y 2With Y 3In only have one for hydrogen, and work as Y 2And Y 3One of when being carboxyl (low alkyl group), carboxyl (low alkyl group that aryl replaces), carbamyl (low alkyl group), carbalkoxy (low alkyl group) or carbalkoxy (low alkyl group that aryl replaces), Y then 2With Y 3In another is a hydrogen or alkyl.Y 2With Y 3Preferably be respectively hydrogen, alkyl, cyano group (low alkyl group), aralkyl, heteroaralkyl, carboxyl (low alkyl group), carboxyl (low alkyl group that aryl replaces) and carbamyl (low alkyl group).
This paper adopts " its any corresponding N-(4-halogen-3-methyl-5-isoxazolyl), N-(4-halogen-5-methyl-3-isoxazolyl), N-(3; 4-dimethyl-5-isoxazolyl), N-(4-halogen-5-methyl-3-isoxazolyl), N-(4-halogen-3-methyl-5-isoxazolyl), N-(4,5-dimethyl-3-isoxazolyl) derivative " to be meant wherein Ar 2The compound identical, but Ar with the compound that offers some clarification on 1Be N-(4-halogen-3-methyl-5-isoxazolyl), N-(4-halogen-5-methyl-3-isoxazolyl), N-(3,4-dimethyl-5-isoxazolyl), N-(4-halogen-5-methyl-3-isoxazolyl), N-(4-halogen-3-methyl-5-isoxazolyl) or N-(4,5-dimethyl-3-isoxazolyl), wherein halogen is any halogenide, and is preferable with Cl or Br.
The abbreviation of any blocking group, amino acid or other compounds that this paper adopted; except as otherwise noted, otherwise be (referring to (1972) according to its general usage, generally acknowledged abbreviation or IUPAC-IUB commission on Biochemical nomenclature (IUPAC-IUB Commission on Biochemical Nomenclature) Biochem.11:942-944).A, be used for the treatment of the compound of the disease that the endothelium peptide regulated
The invention provides the compound of the disease that treatment endothelium peptide regulated and the method for the disease that use formula I compounds for treating endothelium peptide is regulated.Particularly, compound provided by the present invention is thienyl, furyl, pyrryl or the phenyl-sulfamide that aryl replaces, wherein said aryl is four, five or hexabasic, and preferably four or five replace.Particularly preferred sulphonamide is a N-isoxazolyl thiophenesulfonamide, and wherein thiophene replaces through aryl, and this aryl only has one or two hydrogen substituting group.If aryl is quaternary, then preferably be substituted, and one of these substituting groups are polar groups, as hydroxyl, acetoxyl group, carboxyl, alkylsulfonyl, acyl group, heteroaryl, oxime, halogen, pseudohalogen and carboxylic acid amides at 1,2,4 and 6.If aryl is replaced by non-polar group at 2,4 and 6, as alkyl, more specifically be methyl, then aryl preferably five or hexabasic.In five substituted aryls, the 4th substituting group connects thiophene, furans, pyrroles or phenyl ring, and the 5th substituting group polar group preferably, as hydroxyl, acetoxyl group, carboxyl, alkylsulfonyl, acyl group, heteroaryl, oxime, halogen, pseudohalogen and carboxylic acid amides.
Compound described here has good bioavailability in animal model and other appropriate model in vivo, the interior transformation period of Chang body, and good usefulness relatively.
In this specifically described embodiment, Ar 1Be 3-or 5-isoxazolyl, and this sulfonamide compounds has formula III: Or acceptable derivates, wherein R on its pharmacology 1And R 2Be following (i), (ii) or (iii):
(i) R 1And R 2Be independently selected from respectively in H, NH 2, NO 2Halogen; pseudohalogen; alkyl; alkenyl; alkynyl group; aryl; aralkyl; heteroaryl; alkoxyl group; alkylamino; alkylthio; alkyl oxy; haloalkyl; the alkyl sulfinyl; alkyl sulphonyl; aryloxy; arylamino; arylthio; the aryl sulfinyl; aryl sulfonyl; haloalkyl; halogenated aryl; carbalkoxy; alkyl-carbonyl; aminocarboxyl; aryl carbonyl; formyl radical; replace or the sunsubstituting formyl amine base; and replacement or unsubstituted urea groups; alkyl wherein; alkenyl and 1-14 carbon atom of alkynyl group part phenyl ring; and can be straight or branched or cyclic; and 4-16 carbon atom of aryl moiety phenyl ring, but R 2Not halogen or pseudohalogen; Perhaps
(ii) R 1And R 2Formation-(CH together 2) n-, wherein n is 3-6; Perhaps
(iii) R 1And R 2Form the 1,3-butadiene base together (CH=CH-CH=CH-);
M is-C (Y)-W-(CH 2) mC (Y) (CH 2) r, (CH 2) mC (Y) NH (CH 2) r, (CH 2) m(CH=CH) (CH 2) r, (CH 2) mC (Y) (CH 2) sNH (CH 2) r, C=N (OH) (CH 2) r, (CH 2) mC (Y) (CH=CH) sNH (CH 2) r, CH (OH) (CH 2) r, CH (CH 3) C (Y) (CH 2) r, CH (CH 3) C (Y) (CH 2) m(CH=CH) (CH 2) r, (CH 2) r, (CH 2) rO, (CH 2) S (O) nWherein n is 0-2, and wherein m, s and r are 0-6 respectively independently, are preferably 0-3, and wherein W is O, NH or (CH 2) zWherein z is 0-6, is preferably 0-3, more preferably 1; And Y is O, S, perhaps with R 8And the atom that they connected forms 3-16 unit not replacement or substituted ring or heterocycle together, is preferably 5 or 6 yuan of not replacement or substituted ring or heterocycles, and more preferably 6 yuan do not replace or substituted heterocycle; M preferably-C (Y)-W-or (CH 2) z
R 3And R 4Be independently selected from hydrogen, halogen, cyano group, cyano group alkyl, C (O) R 41, alkyl, alkenyl, cycloalkyl and aryl, or form alkylidene group or alkenylene, wherein R together 41Be alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkyl amido, arylamino, ammonia diaryl base, alkyl sulfonyl-amino, arlysulfonylamino, alkyl sulphonyl alkylamino, alkyl sulphonyl arylamino, aryl sulfonyl alkylamino or aryl sulfonyl arylamino;
Y 1And Y 2Be respectively carbon or nitrogen independently; A and b are respectively 0 or 1 independently;
R 5, R 6, R 7, R 8And R 9Be independently selected from following (i) respectively or (ii):
(i) R 5, R 6, R 7, R 8And R 9Be independently selected from H OH, NHR respectively 38, CONR 38R 39, NO 2, cyano group, halogen, pseudohalogen, alkyl; alkenyl, alkynyl group, aryl, aralkyl, heteroaryl; alkoxyl group, alkylamino, alkylthio, haloalkyl, alkyl sulfinyl; alkyl sulphonyl, carbalkoxy, alkyl-carbonyl, alkenyl thio; alkenyl amino, alkenyl oxy, alkenyl sulfinyl, alkenyl alkylsulfonyl; carbalkoxy, aromatic yl aminocarbonyl, alkylamino-carbonyl, aminocarboxyl; (alkyl-aminocarboxyl) alkyl, acetoxyl group, hydroxyl, carboxyl; carboxyalkyl, carboxyl thiazolinyl, alkyl sulfonyl-amino alkyl, cyano group alkyl; ethanoyl, acetoxyl group alkyl, hydroxyalkyl, alkoxyl group alkoxyl group; hydroxyalkyl, (acetoxyl group) alkoxyl group, (hydroxyl) alkoxyl group, formyl radical; SULPHURYL CHLORIDE, amino acid, hexose, O-glycosides; ribose, low alkyl group, CN ,-(CH 2) xC (O) (CH 2) yCH 3,-(CH 2) xCH 3, (CH 2) xThe NH-low alkyl group ,-(CH 2) xC (O) NH 2, D-, L-or DL-Amino Acid, uncle or secondary amide, O-glycosides, hexose or ribose ,-S (O) 2NH 2, hydroxyl, alkoxyl group, carbalkoxy, acetoxyl group alkyl ,-(CH 2) xCOOH ,-(CH 2) xCH (COOH) (CH 2) yCH 3, CO 2-low alkyl group, CN, heteroaryl, C (O) (CH 2) xS (O) 2(CH 2) yCH 3, C (=N-OR 38) (CH 2) yCH 3,-C (O) C (O) (CH 2) yCH 3,-(CH 2) xN (CH 3) 2, S (O) 2NHR 50, OS (O) 2NR 38R 39, alkylaryl, miscellaneous alkyl aryl, C (O) NHR 30,-(CH 2) xOH, and-C (O) N (H) N (H) R 50
R wherein 38And R 39Be independently selected from respectively in hydrogen, alkyl, alkenyl, alkynyl group, aryl, haloalkyl, alkylaryl, heterocyclic radical, aralkyl, alkoxy aryl, alkoxyl group, aryloxy, cycloalkyl, cycloalkenyl group and cycloalkynyl radical, and preferably be selected from hydrogen respectively, low alkyl group, lower alkoxy and low-grade halogenated alkyl; X and y are respectively 0-14 independently; And R 50It is substituting group such as hydrogen, low alkyl group, lower alkoxy or heteroaryl; Perhaps
The (ii) R of the adjacent carbons on the substituted ring 5, R 6, R 7, R 8And R 9In at least two form alkylenedioxy group, alkylidene group sulfo-oxygen base oxygen base or alkylidene group dithio oxygen base together (as-O-(CH 2) n-O-,-S-(CH 2) n-O-,-S-(CH 2) n-S-, wherein n is 1-4, is preferably 1 or 2), it is not replace or be substituted by replacing one or more hydrogen with halogen, low alkyl group, lower alkoxy or junior alkyl halides, and other R 5, R 6, R 7, R 8And R 9Select as (i); And
X is-C (R 3)=C (R 4)-, S, O or NR 11, R wherein 11Be hydrogen or comprise maximum 30 carbon atoms, preferred 1-10 carbon atom, more preferably 1-6 carbon atom, and be selected from hydrogen, alkyl, alkenyl, alkynyl group, aryl, alkylaryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, C (O) R 15And S (O) nR 15Wherein n is 0-2; R 15Be hydrogen, alkyl, alkenyl, alkynyl group, aryl, alkylaryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group or cycloalkynyl radical; R 11And R 15Be not replace or replaced by one or more substituting group that is selected from respectively among the z, described Z comprises hydrogen, halogen, pseudohalogen, alkyl, alkoxyl group, alkenyl, alkynyl group, aryl, amino acid, primary and secondary acid amides, O-glycosides, hexose, ribose, alkylaryl, miscellaneous alkyl aryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, OH, CN, C (O) R 16, OC (O) R 16, CO 2R 16, OCO 2R 16, SH, S (O) nR 16Wherein n is 0-2, NHOH, NR 12R 16, NO 2, N 3, OR 16, R 12NCOR 16And CONR 12R 16R 16Be hydrogen, alkyl, alkenyl, alkynyl group, aryl, alkylaryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, chlorine, NH 50, alkylaryl, miscellaneous alkyl aryl or-(CH 2) xOH; R 50It is substituting group such as hydrogen, low alkyl group, lower alkoxy or heteroaryl; X is 0-14; R 12Be selected from R 11And Z, and be selected from hydrogen, alkyl, alkenyl, alkynyl group, aryl, alkylaryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, C (O) R 17And S (O) nR 17Wherein n is 0-2; R 17Be hydrogen, alkyl, alkenyl, alkynyl group, aryl, alkylaryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group or cycloalkynyl radical; R 12And R 16Can form alkylidene group together; R 11, R 12, R 15And R 16Can distinguish further and be replaced by the proper group among the Z.
In all embodiments, X preferably S or-C (R 3)=C (R 4)-, be more preferably S or-CH=CH-, and most preferably be S.
In one embodiment, M preferably-C (Y)-W-, and used compound has with following formula IV in said composition and method:
Figure A0081806100591
Or acceptable derivates, wherein R on its pharmacology 1-R 9, X, Y, W, Y 1, Y 2, a and b respectively as defined above.
In these embodiments, compound is preferably the compound of formula IV, wherein X be S or-CH=CH-, be preferably S; R 1Be halogen or low alkyl group; R 2It is low alkyl group; R 3And R 4Be respectively hydrogen; R 5Be low alkyl group or-(CH 2) xC (O) (CH 2) yCH 3R 6Be low alkyl group ,-(CH 2) xC (O) (CH 2) yCH 3, or heteroaryl; R 7Be hydrogen, hydroxyl, alkoxyl group, low alkyl group, S (O) 2NHR 50And OS (O) 2NR 38R 39
R wherein 38And R 39Be independently selected from respectively in hydrogen, alkyl, alkenyl, alkynyl group, aryl, haloalkyl, alkylaryl, heterocyclic radical, aralkyl, alkoxy aryl, alkoxyl group, aryloxy, cycloalkyl, cycloalkenyl group and cycloalkynyl radical, and preferably be selected from hydrogen respectively, low alkyl group, lower alkoxy and low-grade halogenated alkyl; X and y are respectively 0-14 independently; And R 50Be hydrogen, low alkyl group, lower alkoxy or heteroaryl;
Y and R 8Be selected from following (i) or (ii):
(i) Y is O; And R 8Be CONR 38R 39, CN, heteroaryl, alkyl sulphonyl, (CH 2) xC (O) (CH 2) yCH 3, alkyl, halogen, pseudohalogen, hydroxyalkyl, C (O) (CH 2) xS (O) 2(CH 2) yCH 3Or C (=N-OR 38) (CH 2) yCH 3Perhaps
(ii) Y and R 8Form 3-16 unit not replacement or substituted ring or heterocycle with the atom that they connected, preferred 5 or 6 yuan of not replacement or substituted ring or heterocycles, more preferably 6 yuan do not replace or substituted heterocycle Y and R 8Preferably together formation-CO-N=or-CO-C (CN)=;
R 9Be H; Y 1And Y 2Be respectively carbon or nitrogen independently; If Y 2Be carbon, then a is 1; If Y 2Be nitrogen, then a is 0; If Y 1Be carbon, then b is 1; If Y 1Be nitrogen, then b is 0; And W is NH.
In particularly preferred embodiments, the compound of formula IV is the 2-replacement-3-sulphonamide with following formula V: And acceptable derivates on the pharmacology, wherein X be S or-CH=CH-, be preferably S; R 1Be halogen or low alkyl group; R 2It is low alkyl group; R 3And R 4Be respectively hydrogen; R 5Be low alkyl group or-(CH 2) xC (O) (CH 2) yCH 3R 6Be low alkyl group ,-(CH 2) xC (O) (CH 2) yCH 3, or heteroaryl; R 7Be hydrogen, hydroxyl, alkoxyl group, low alkyl group, S (O) 2NHR 50And OS (O) 2NR 38R 39
R wherein 38And R 39Be independently selected from respectively in hydrogen, alkyl, alkenyl, alkynyl group, aryl, haloalkyl, alkylaryl, heterocyclic radical, aralkyl, alkoxy aryl, alkoxyl group, aryloxy, cycloalkyl, cycloalkenyl group and cycloalkynyl radical, and preferably be selected from hydrogen respectively, low alkyl group, lower alkoxy and low-grade halogenated alkyl; X and y are respectively 0-14 independently; And R 50Be hydrogen, low alkyl group, lower alkoxy or heteroaryl;
Y and R 8Be selected from following (i) or (ii):
(i) Y is O; And R 8Be CONR 38R 39, CN, heteroaryl, alkyl sulphonyl, (CH 2) xC (O) (CH 2) yCH 3, alkyl, halogen, pseudohalogen, hydroxyalkyl, C (O) (CH 2) xS (O) 2(CH 2) yCH 3Or C (=N-OR 38) (CH 2) yCH 3Or
(ii) Y and R 8Form 3-16 unit not replacement or substituted ring or heterocycle with the atom that they connected, preferably a 5 or 6 yuan are replacement or substituted ring or heterocycle not, and more preferably 6 yuan do not replace or substituted heterocycle Y and R 8Preferably together formation-CO-N=or-CO-C (CN)=;
R 9Be H; Y 1And Y 2Be respectively carbon or nitrogen independently; If Y 2Be carbon, then a is 1; If Y 2Be nitrogen, then a is 0; If Y 1Be carbon, then b is 1; If Y 1Be nitrogen, then b is 0; And W is NH.
In a more preferred embodiment, described compound is the compound of formula V, wherein R 1Be halogen or low alkyl group; Preferably Cl or Me; Be more preferably Me.In these embodiments, R 2Be low alkyl group, Me preferably; And R 3And R 4Be respectively H.
In specifically described embodiment, described compound is following formula V compound, wherein R 5Be Me or ethanoyl, be preferably Me; R 6Be Me, ethanoyl or 2-oxazolyl, be preferably Me; R 7Be H, Me, OSO 2NMe 2, OCH 2-cyclopropyl, hydroxyl or SO 2NH-(4-chloro-3-methyl-5-isoxazolyl), preferably H;
Y and R 8Be selected from (i) or (ii), be preferably as follows and be selected from (i):
(i) Y is O; And R 8Be C (O) CH 2SO 2CH 3, C (O) Me, CN, C (O) N (Me) (CH 2-t-Bu), SO 2Me, 2-oxazolyl, SO 2-sec.-propyl, SO 2-n-propyl group, CH (OH) Me, C (O) NMe 2, C (=N-OMe) Me, Me, C (O) Et, Cl, n-propyl group or ethyl; Or
(ii) Y and R 8Together formation-CO-N=or-CO-C (CN)=;
R 9Be H; Y 1And Y 2Be respectively carbon or nitrogen, preferably carbon independently; If Y 2Be carbon, then a is 1; If Y 2Be nitrogen, then a is 0; If Y 1Be carbon, then b is 1; If Y 1Be nitrogen, then b is 0; And W is NH.
Therefore, in preferred embodiments, compound is following formula V compound, and wherein X is S; R 1Be Cl or Me, be preferably Me; R 2Be Me; R 3, R 4And R 9Be H; Y is O; W is NH; And Y 1And Y 2Be respectively carbon.In these embodiments, compound is the thiophene sulfonamide compounds with following formula VI:
Figure A0081806100621
Or acceptable derivates, wherein R on its pharmacology 1Be Cl or Me, preferably Me; R 5Be Me or ethanoyl, preferably Me; R 6Be Me, ethanoyl or 2-oxazolyl, preferably Me; R 7Be H, Me, OSO 2NMe 2, OCH 2-cyclopropyl, hydroxyl or SO 2NH-(4-chloro-3-methyl-5-isoxazolyl), preferably H; And R 8Be C (O) CH 2SO 2CH 3, C (O) Me, CN, C (O) N (Me) (CH 2-t-Bu), SO 2Me, 2-oxazolyl, SO 2-sec.-propyl, SO 2-n-propyl group, CH (OH) Me, C (O) NMe 2, C (=N-OMe) Me, Me, C (O) Et, Cl, n-propyl group or ethyl.
In the most preferred embodiment, R 1, R 5And R 6Be Me; R 7Be hydrogen; And R 8Be C (O) Me.
In another embodiment, compound is Y wherein 1And Y 2Be respectively the formula I compound of nitrogen.In this embodiment, a and b are preferably 0; And other variable as defined above.In preferred embodiments, R 5, R 6And R 8Be alkyl, preferably low alkyl group is more preferably Me; Y is O; And W is NH.In a more preferred embodiment, R 3And R 4Be respectively H; And X is S.Therefore, the compound of this embodiment is N-(5-isoxazolyl) 2-or 3-(5-pyrimidinyl-amino carbonyl) thiophenesulfonamide.
The preferred compound of above-mentioned embodiment comprises N-(2-ethanoyl-4; the 6-3,5-dimethylphenyl)-3-{[(3; 4-dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides; N-(2-cyano group-3; 4; the 6-trimethylphenyl)-3-{[(3; 4-dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(3; 4; 6-trimethylammonium-2-propionyl phenyl)-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-[2-(1-hydroxyethyl)-4; the 6-3,5-dimethylphenyl]-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the N-{2-[(dimethylamino) carbonyl]-4; the 6-3,5-dimethylphenyl)-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-{2; 4-dimethyl-6-[(methoxyl group) ethanimidoyl] phenyl }-the 2-thiophenecarboxamides; 3-{[(3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-sulfur phenenyl) carbonyl] amino }-2; 4; 6-trimethylphenyl-N; N-dimethylamino sulphonate; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-{3-[(cyclopropyl methyl) the oxygen base]-2; 4; the 6-trimethylphenyl }-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2; 4; 6-trimethylammonium-5-pyrimidyl)-the 2-thiophenecarboxamides; N-(2-ethanoyl-3; 4; the 6-trimethylphenyl)-and 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2-cyano group-3; 4; the 6-trimethylphenyl)-the 2-thiophenecarboxamides; N-(2-chloro-4; the 6-3,5-dimethylphenyl)-and 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(4; 6-diacetyl-3-hydroxyl-2-propyl group phenyl-2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2; 4-dimethyl-6-[2-(methyl sulphonyl) ethanoyl] phenyl }-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2; 4-dimethyl-6-{[methyl (2; the 2-dimethyl propyl) amino] carbonyl } phenyl)-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl)-N-[2; 4-dimethyl-6-(methyl sulphonyl) phenyl]-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-[2; 4-dimethyl-6-(1; 3-oxazole-2-yl) phenyl]-the 2-thiophenecarboxamides; 3-{[(4-chloro-5-isoxazolyl) amino] alkylsulfonyl }-N-[2-(2-sulfonyl propyl base)-4; the 6-3,5-dimethylphenyl]-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl)-N-[2; 4-dimethyl-6-(sulfonyl propyl base) phenyl]-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2-ethyl-4; the 6-3,5-dimethylphenyl)-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-[2; 6-dimethyl-4-(1; 3-oxazole-2-yl) phenyl]-the 2-thiophenecarboxamides; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6; 8-dimethyl-4-hydroxyl-2-benzo pyrimidyl) thiophene-3-sulphonamide and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyano group-4-hydroxyl-6,8-dimethylbiphenyl [b] pyridine-2-yl) thiophene-3-sulphonamide.
In another embodiment, X is-C (R 3)=C (R 4)-, and compound is the benzsulfamide of formula VII:
Figure A0081806100641
And acceptable derivates on the pharmacology, wherein R 1And R 2Be respectively following (i), (ii) or (iii):
(i) R 1And R 2Be independently selected from respectively in H, NH 2, NO 2Halogen; pseudohalogen; alkyl; alkenyl; alkynyl group; aryl; aralkyl; heteroaryl; alkoxyl group; alkylamino; alkylthio; alkyl oxy; haloalkyl; the alkyl sulfinyl; alkyl sulphonyl; aryloxy; arylamino; arylthio; the aryl sulfinyl; aryl sulfonyl; haloalkyl; halogenated aryl; carbalkoxy; alkyl-carbonyl; aminocarboxyl; aryl carbonyl; formyl radical; replace or the sunsubstituting formyl amine base; and replace or do not replace urea groups; alkyl wherein; alkenyl and alkynyl group partly comprise 1-14 carbon atom; and can be straight or branched or cyclic; and aryl moiety comprises 4-16 carbon atom, but R 2Not halogen or pseudohalogen; Or
(ii) R 1And R 2Formation-(CH together 2) n-, wherein n is 3-6; Or
(iii) R 1And R 2Form the 1,3-butadiene base together (CH=CH-CH=CH-);
W is O, NH or (CH 2) zWherein z is 0-6, is preferably 0-3, more preferably 1; And Y is O, S, perhaps forms 3-16 unit not replacement or substituted ring or heterocycle with R8 and atom that they connected, preferred 5 or 6 yuan of not replacement or substituted ring or heterocycles, and more preferably 6 yuan do not replace or substituted heterocycle; M preferably-C (Y)-W-or (CH 2) z
R 3And R 4Be independently selected from hydrogen halogen, cyano group, cyano group alkyl, C (O) R 41, alkyl, alkenyl, cycloalkyl and aryl, or form alkylidene group or alkenylene, wherein R together 41Be alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkyl amido, arylamino, ammonia diaryl base, alkyl sulfonyl-amino, arlysulfonylamino, alkyl sulphonyl alkylamino, the alkyl sulphonyl arylamino, aryl sulfonyl alkylamino or aryl sulfonyl arylamino;
Y 1And Y 2Be respectively carbon or nitrogen independently; A and b are respectively 0 or 1 independently;
R 5, R 6, R 7, R 8And R 9Following independently respectively be selected from (i) or (ii):
(i) R 5, R 6, R 7, R 8And R 9Be independently selected from H OH, NHR respectively 38, CONR 38R 39, NO 2, cyano group, halogen, pseudohalogen, alkyl; alkenyl, alkynyl group, aryl, aralkyl, heteroaryl; alkoxyl group, alkylamino, alkylthio, haloalkyl, alkyl sulfinyl; alkyl sulphonyl, carbalkoxy, alkyl-carbonyl, alkenyl thio; alkenyl amino, alkenyl oxy, alkenyl sulfinyl, alkenyl alkylsulfonyl; carbalkoxy, aromatic yl aminocarbonyl, alkylamino-carbonyl, aminocarboxyl; (alkyl-aminocarboxyl) alkyl, acetoxyl group, hydroxyl, carboxyl; carboxyalkyl, carboxyl thiazolinyl, alkyl sulfonyl-amino alkyl, cyano group alkyl; ethanoyl, acetoxyl group alkyl, hydroxyalkyl, alkoxyl group alkoxyl group; hydroxyalkyl, (acetoxyl group) alkoxyl group, (hydroxyl) alkoxyl group, formyl radical; SULPHURYL CHLORIDE, amino acid, hexose, O-glycosides; ribose, low alkyl group, CN ,-(CH 2) xC (O) (CH 2) yCH 3,-(CH 2) xCH 3, (CH 2) xThe NH-low alkyl group ,-(CH 2) xC (O) NH 2, D-, L-or DL-Amino Acid, uncle or secondary amide, O-glycosides, hexose or ribose ,-S (O) 2NH 2, hydroxyl, alkoxyl group, carbalkoxy, acetoxyl group alkyl ,-(CH 2) xCOOH ,-(CH 2) xCH (COOH) (CH 2) yCH 3, CO 2-low alkyl group, CN, heteroaryl, C (O) (CH 2) xS (O) 2(CH 2) yCH 3, C (=N-OR 38) (CH 2) yCH 3,-C (O) C (O) (CH 2) yCH 3,-(CH 2) xN (CH 3) 2, S (O) 2NHR 50, OS (O) 2NR 38R 39, alkylaryl, miscellaneous alkyl aryl, C (O) NHR 50,-(CH 2) xOH, and-C (O) N (H) N (H) R 50
R wherein 38And R 39Be independently selected from respectively in hydrogen, alkyl, alkenyl, alkynyl group, aryl, haloalkyl, alkylaryl, heterocyclic radical, aralkyl, alkoxy aryl, alkoxyl group, aryloxy, cycloalkyl, cycloalkenyl group and cycloalkynyl radical, and preferably be selected from hydrogen respectively, low alkyl group, lower alkoxy and low-grade halogenated alkyl; X and y are respectively 0-14 independently; And R 50It is substituting group such as hydrogen, low alkyl group, lower alkoxy or heteroaryl; Or
The (ii) R of adjacent atom on the substituted ring 5, R 6, R 7, R 8And R 9In have at least two to form alkylenedioxy group, alkylidene group sulfo-oxygen base oxygen base or alkylidene group dithio oxygen base together (as-O-(CH 2) n-O-,-S-(CH 2) n-O-,-S-(CH 2) n-S-, wherein n is 1-4, is preferably 1 or 2) it is not replace or be substituted by replacing one or more hydrogen with halogen, low alkyl group, lower alkoxy or junior alkyl halides, and other R 5, R 6, R 7, R 8And R 9Described in (i), select.
In certain embodiments, the formula VII compound that the compound formula is following, wherein R 3, R 4And R 9Be H; Y is O; And W is NH.In preferred embodiments, R 1And R 2Be selected from alkyl, low-grade alkenyl, alkynyl of low-grade chain, low-grade halogenated alkyl, halogen, pseudohalogen or H respectively, but R 2It or not halogen.R 1Preferably low alkyl group or halogen are more preferably Me or Cl.R 2Preferably low alkyl group is more preferably Me.
In a more preferred embodiment, compound has with following formula VIII: Or acceptable derivates, wherein R on its pharmacology 1Be low alkyl group or halogen, preferably Me or Cl; R 5Be low alkyl group or-(CH 2) xC (O) (CH 2) yCH 3R 6Be low alkyl group ,-(CH 2) xC (O) (CH 2) yCH 3, or heteroaryl; R 7Be hydrogen, hydroxyl, alkoxyl group, low alkyl group, S (O) 2NHR 50Or OS (O) 2NR 38R 39And R 8Be CONR 38R 39, CN, heteroaryl, alkyl sulphonyl, (CH 2) xC (O) (CH 2) yCH 3, alkyl, halogen, pseudohalogen, hydroxyalkyl, C (O) (CH 2) xS (O) 2(CH 2) yCH 3Or C (=N-OR 38) (CH 2) yCH 3
In a more preferred embodiment, described compound is following formula VIII compound, wherein R 5Be Me or ethanoyl, be preferably Me; R 6Be Me, ethanoyl or 2-oxazolyl, be preferably Me; R 7Be H, Me, OSO 2NMe 2, OCH 2-cyclopropyl, hydroxyl or SO 2NH-(4-chloro-3-methyl-5-isoxazolyl) is preferably H; And R 8Be C (O) CH 2SO 2CH 3, C (O) Me, CN, C (O) N (Me) (CH 2-t-Bu), SO 2Me, 2-oxazolyl, SO 2-sec.-propyl, SO 2-n-propyl group, CH (OH) Me, C (O) NMe 2, C (=N-OMe) Me, Me, C (O) Et, Cl, n-propyl group or ethyl.Therefore, in preferred embodiments, described compound is following formula VIII compound, wherein R 5And R 6Be Me; And R 7Be H.In these embodiments, R 8Most preferably be C (O) Me.
Preferred formula VIII compound comprises N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-ethanoyl-4,6-3,5-dimethylphenyl aminocarboxyl) benzsulfamide.
In other embodiment, described compound is following formula I compound, and wherein M is (CH 2) z, wherein z is 0-6, preferred 0-3, more preferably 1.Therefore, in a more preferred embodiment, the compound of formula I has formula IX:
Figure A0081806100681
Or acceptable derivates, wherein R on its pharmacology 1And R 2Be following (i), (ii) or (iii):
(i) R 1And R 2Be independently selected from respectively in H, NH 2, NO 2Halogen; pseudohalogen; alkyl; alkenyl; alkynyl group; aryl; aralkyl; heteroaryl; alkoxyl group; alkylamino; alkylthio; alkyl oxy; haloalkyl; the alkyl sulfinyl; alkyl sulphonyl; aryloxy; arylamino; arylthio; the aryl sulfinyl; aryl sulfonyl; haloalkyl; halogenated aryl; carbalkoxy; alkyl-carbonyl; aminocarboxyl; aryl carbonyl; formyl radical; replace or the sunsubstituting formyl amine base; and replace or do not replace urea groups; alkyl wherein; alkenyl and alkynyl group partly comprise 1-14 carbon atom; and can be straight or branched or cyclic; and aryl moiety comprises 4-16 carbon atom, but R 2Not halogen or pseudohalogen; Or
(ii) R 1And R 2Formation-(CH together 2) n-, wherein n is 3-6; Or,
(iii) R 1And R 2Form the 1,3-butadiene base together (CH=CH-CH=CH-);
R 3And R 4Be independently selected from hydrogen, halogen, cyano group, cyano group alkyl, C (O) R 41, alkyl, alkenyl, cycloalkyl and aryl, or form alkylidene group or alkenylene, wherein R together 41Be alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkyl amido, arylamino, ammonia diaryl base, alkyl sulfonyl-amino, arlysulfonylamino, alkyl sulphonyl alkylamino, alkyl sulphonyl arylamino, aryl sulfonyl alkylamino or aryl sulfonyl arylamino;
Y 1And Y 2Be respectively carbon or nitrogen independently; A and b are respectively 0 or 1 independently;
R 5, R 6, R 7, R 8And R 9Following independently respectively be selected from (i) or (ii):
(i) R 5, R 6, R 7, R 8And R 9Be independently selected from H OH, NHR respectively 38, CONR 38R 39, NO 2, cyano group, halogen, pseudohalogen, alkyl; alkenyl, alkynyl group, aryl, aralkyl, heteroaryl; alkoxyl group, alkylamino, alkylthio, haloalkyl, alkyl sulfinyl; alkyl sulphonyl, carbalkoxy, alkyl-carbonyl, alkenyl thio; alkenyl amino, alkenyl oxy, alkenyl sulfinyl, alkenyl alkylsulfonyl; carbalkoxy, aromatic yl aminocarbonyl, alkylamino-carbonyl, aminocarboxyl; (alkyl-aminocarboxyl) alkyl, acetoxyl group, hydroxyl, carboxyl; carboxyalkyl, carboxyl thiazolinyl, alkyl sulfonyl-amino alkyl, cyano group alkyl; ethanoyl, acetoxyl group alkyl, hydroxyalkyl, alkoxyl group alkoxyl group; hydroxyalkyl, (acetoxyl group) alkoxyl group, (hydroxyl) alkoxyl group, formyl radical; SULPHURYL CHLORIDE, amino acid, hexose, O-glycosides; ribose, low alkyl group, CN ,-(CH 2) xC (O) (CH 2) yCH 3,-(CH 2) xCH 3, (CH 2) xThe NH-low alkyl group ,-(CH 2) xC (O) NH 2, D-, L-or DL-Amino Acid, uncle or secondary amide, O-glycosides, hexose or ribose ,-S (O) 2NH 2, hydroxyl, alkoxyl group, carbalkoxy, acetoxyl group alkyl ,-(CH 2) xCOOH ,-(CH 2) xCH (COOH) (CH 2) yCH 3, CO 2-low alkyl group, CN, heteroaryl, C (O) (CH 2) xS (O) 2(CH 2) yCH 3, C (=N-OR 38) (CH 2) yCH 3,-C (O) C (O) (CH 2) yCH 3,-(CH 2) xN (CH 3) 2, S (O) 2NHR 50, OS (O) 2NR 38R 39, alkylaryl, miscellaneous alkyl aryl, C (O) NHR 50,-(CH 2) xOH, and-C (O) N (H) N (H) R 50
R wherein 38And R 39Be independently selected from respectively in hydrogen, alkyl, alkenyl, alkynyl group, aryl, haloalkyl, alkylaryl, heterocyclic radical, aralkyl, alkoxy aryl, alkoxyl group, aryloxy, cycloalkyl, cycloalkenyl group and cycloalkynyl radical, and preferably be selected from hydrogen respectively, low alkyl group, lower alkoxy and low-grade halogenated alkyl; X and y are respectively 0-14 independently; And R 50It is substituting group such as hydrogen, low alkyl group, lower alkoxy or heteroaryl; Or
The (ii) R of adjacent atom on the substituted ring 5, R 6, R 7, R 8And R 9In have at least two to form alkylenedioxy group, alkylidene group sulfo-oxygen base oxygen base or alkylidene group dithio oxygen base together (as-O-(CH 2) n-O-,-S-(CH 2) n-O-,-S-(CH 2) n-S-, wherein n is 1-4, is preferably 1 or 2), it is not replace or be substituted by replacing one or more hydrogen with halogen, low alkyl group, lower alkoxy or junior alkyl halides, and other R 5, R 6, R 7, R 8And R 9Described in (i), select; And
X is-C (R 3)=C (R 4)-, S, O or NR 11, R wherein 11Be hydrogen or comprise maximum 30, preferred 1-10, more preferably 1-6 carbon atom, and be selected from hydrogen, alkyl, alkenyl, alkynyl group, aryl, alkylaryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, C (O) R 15And S (O) nR 15Wherein n is 0-2; R 15Be hydrogen, alkyl, alkenyl, alkynyl group, aryl, alkylaryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group or cycloalkynyl radical; R 11And R 15Be not replace or replaced by one or more substituting group that is independently selected from respectively in Z, described Z comprises hydrogen, halogen, pseudohalogen, alkyl, alkoxyl group, alkenyl, alkynyl group, aryl, amino acid, primary and secondary acid amides, O-glycosides, hexose, ribose, alkylaryl, miscellaneous alkyl aryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, OH, CN, C (O) R 16, OC (O) R 16, CO 2R 16, OCO 2R 16, SH, S (O) nR 16Wherein n is 0-2, NHOH, NR 12R 16, NO 2, N 3, OR 16, R 12NCOR 16And CONR 12R 16: R 16Be hydrogen, alkyl, alkenyl, alkynyl group, aryl, alkylaryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, chlorine, NHR 50, alkylaryl, miscellaneous alkyl aryl or-(CH 2) xOH; R 50It is substituting group such as hydrogen, low alkyl group, lower alkoxy or heteroaryl; X is 0-14; R 12Be independently selected from R 11And Z, be selected from hydrogen, alkyl, alkenyl, alkynyl group, aryl, alkylaryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, C (O) R 17And S (O) nR 17Wherein n is 0-2; R 17Be hydrogen, alkyl, alkenyl, alkynyl group, aryl, alkylaryl, heterocyclic radical, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl group or cycloalkynyl radical; R 12And R 16Can form alkylidene group together; R 11, R 12, R 15And R 16Can distinguish further and be replaced by defined proper group among the Z.
In these embodiments, R 3And R 4Be preferably formed-CH=CH-CH=CH-, and X S preferably.In a more preferred embodiment, the compound of formula LX is 2 thionaphthene that is replaced by benzyl-3-sulfonamide substitutions.Therefore, in a more preferred embodiment, the compound of formula IX has formula X:
Figure A0081806100721
Or acceptable derivates, wherein R on its pharmacology 1And R 2Following respectively is (i), (ii) or (iii):
(i) R 1And R 2Be independently selected from respectively in H, NH 2, NO 2Halogen; pseudohalogen; alkyl; alkenyl; alkynyl group; aryl; aralkyl; heteroaryl; alkoxyl group; alkylamino; alkylthio; alkyl oxy; haloalkyl; the alkyl sulfinyl; alkyl sulphonyl; aryloxy; arylamino; arylthio; the aryl sulfinyl; aryl sulfonyl; haloalkyl; halogenated aryl; carbalkoxy; alkyl-carbonyl; aminocarboxyl; aryl carbonyl; formyl radical; replace or the sunsubstituting formyl amine base; and replace or do not replace urea groups; alkyl wherein; alkenyl and alkynyl group partly comprise 1-14 carbon atom; and can be straight or branched or cyclic; and aryl moiety comprises 4-16 carbon atom, but R 2Not halogen or pseudohalogen; Or,
(ii) R 1And R 2Formation-(CH together 2) n-, wherein n is 3-6; Or,
(iii) R 1And R 2Form the 1,3-butadiene base together (CH=CH-CH=CH-);
Y 1And Y 2Be respectively carbon or nitrogen independently; A and b are respectively 0 or 1 independently;
R 5, R 6, R 7, R 8And R 9Following independently respectively be selected from (i) or (ii):
(i) R 5, R 6, R 7, R 8And R 9Be independently selected from H OH, NHR respectively 38, CONR 38R 39, NO 2, cyano group, halogen, pseudohalogen, alkyl; alkenyl, alkynyl group, aryl, aralkyl, heteroaryl; alkoxyl group, alkylamino, alkylthio, haloalkyl, alkyl sulfinyl; alkyl sulphonyl, carbalkoxy, alkyl-carbonyl, alkenyl thio; alkenyl amino, alkenyl oxy, alkenyl sulfinyl, alkenyl alkylsulfonyl; carbalkoxy, aromatic yl aminocarbonyl, alkylamino-carbonyl, aminocarboxyl; (alkyl-aminocarboxyl) alkyl, acetoxyl group, hydroxyl, carboxyl; carboxyalkyl, carboxyl thiazolinyl, alkyl sulfonyl-amino alkyl, cyano group alkyl; ethanoyl, acetoxyl group alkyl, hydroxyalkyl, alkoxyl group alkoxyl group; hydroxyalkyl, (acetoxyl group) alkoxyl group, (hydroxyl) alkoxyl group, formyl radical; SULPHURYL CHLORIDE, amino acid, hexose, O-glycosides; ribose, low alkyl group, CN ,-(CH 2) xC (O) (CH 2) yCH 3,-(CH 2) xCH 3, (CH 2) xThe NH-low alkyl group ,-(CH 2) xC (O) NH 2, D-, L-or DL-Amino Acid, uncle or secondary amide, O-glycosides, hexose or ribose ,-S (O) 2NH 2, hydroxyl, alkoxyl group, carbalkoxy, acetoxyl group alkyl ,-(CH 2) xCOOH ,-(CH 2) xCH (COOH) (CH 2) yCH 3, CO 2-low alkyl group, CN, heteroaryl, C (O) (CH 2) xS (O) 2(CH 2) yCH 3, C (=N-OR 38) (CH 2) yCH 3,-C (O) C (O) (CH 2) yCH 3,-(CH 2) xN (CH 3) 2, S (O) 2NHR 50, OS (O) 2NR 38R 39, alkylaryl, miscellaneous alkyl aryl, C (O) NHR 50,-(CH 2) xOH, and-C (O) N (H) N (H) R 50
R wherein 38And R 39Be independently selected from respectively in hydrogen, alkyl, alkenyl, alkynyl group, aryl, haloalkyl, alkylaryl, heterocyclic radical, aralkyl, alkoxy aryl, alkoxyl group, aryloxy, cycloalkyl, cycloalkenyl group and cycloalkynyl radical, and preferably be selected from hydrogen respectively, low alkyl group, lower alkoxy and low-grade halogenated alkyl; X and y are respectively 0-14 independently; And R 50It is substituting group such as hydrogen, low alkyl group, lower alkoxy or heteroaryl; Or
The (ii) R of adjacent atom on the substituted ring 5, R 6, R 7, R 8And R 9In have at least two to form alkylenedioxy group, alkylidene group sulfo-oxygen base oxygen base or alkylidene group dithio oxygen base together (as-O-(CH 2) n-O-,-S-(CH 2) n-O-,-S-(CH 2) n-S-, wherein n is 1-4, is preferably 1 or 2) it is not replace or be substituted by replacing one or more hydrogen with halogen, low alkyl group, lower alkoxy or junior alkyl halides, and other R 5, R 6, R 7, R 8And R 9Described in (i), select.
In a more preferred embodiment, described compound is following formula X compound, wherein R 1Be halogen or low alkyl group; R 2It is low alkyl group; R 5Be low alkyl group or-(CH 2) xC (O) (CH 2) yCH 3R 6Be low alkyl group ,-(CH 2) xC (O) (CH 2) yCH 3, or heteroaryl; R 7Be hydrogen, hydroxyl, alkoxyl group, low alkyl group, S (O) 2NHR 50And OS (O) 2NR 38R 39
R wherein 38And R 39Be independently selected from respectively in hydrogen, alkyl, alkenyl, alkynyl group, aryl, haloalkyl, alkylaryl, heterocyclic radical, aralkyl, alkoxy aryl, alkoxyl group, aryloxy, cycloalkyl, cycloalkenyl group and cycloalkynyl radical, and preferably be selected from hydrogen respectively, low alkyl group, lower alkoxy and low-grade halogenated alkyl; X and y are respectively 0-14 independently; And R 50Be hydrogen, low alkyl group, lower alkoxy or heteroaryl;
R 8Be CONR 38R 39, CN, heteroaryl, alkyl sulphonyl, (CH 2) xC (O) (CH 2) yCH 3, alkyl, halogen, pseudohalogen, hydroxyalkyl, C (O) (CH 2) xS (O) 2(CH 2) yCH 3Or C (=N-OR 38) (CH 2) yCH 3
R 9Be H; Y 1And Y 2Be respectively carbon or nitrogen independently; If Y 2Be carbon, then a is 1; If Y 2Be nitrogen, then a is 0; If Y 1Be carbon, then b is 1; And if Y 1Be nitrogen, then b is 0.
In these embodiments, Y 1And Y 2Carbon preferably; A and b are respectively 1; R 5, R 6And R 8Preferably low alkyl group, more preferably Me; And R 7Preferably H or SO 2NHR 50, R wherein 50Be heteroaryl, more preferably isoxazolyl most preferably is 4-chloro-3-methyl-5-isoxazolyl.
The preferred compound of this embodiment comprises N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2; 4; the 6-trimethyl benzyl) benzo [b] thiophene-3-sulphonamide and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(4-chloro-3-methyl-5-isoxazolyl) amino-sulfonyl-2; 4, the 6-trimethyl benzyl) benzo [b] thiophene-3-sulphonamide.
Also interesting is acceptable derivates on the pharmacology, comprises salt, ester, bronsted lowry acids and bases bronsted lowry, solvate, hydrate and the prodrug of sulfonamide compounds.Preferably acceptable salt, particularly an alkali metal salt on the pharmacology most preferably are sodium salts.
Particularly preferred derivative is the salt of following compound, and wherein W is an alkylidene group, more especially CH 2In these derivatives, preferred salt is sodium salt.
In all embodiments, but also reference table 1 is definite for preferred substituted, and this table has shown-a little exemplary compounds.Preferred compound be have in the table 1 the most highly active those, preferred substituted then is the substituting group on the compound with high reactivity (activity under the minimum concentration).
Table 1
Compound ??ET AActive *
N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylene-dioxy)-6-aminomethyl phenyl) ethanoyl]-thiophene-3-sulphonamide ????1.0
N-(2-ethanoyl-4,6-3,5-dimethylphenyl)-3-{[(3,4 dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides ????18.1
N-(2-ethanoyl-4,6-3,5-dimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenesulfonamide ????38.0
N-(2-cyano group-3,4,6-trimethylphenyl)-3-{[(3,4-dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides ????18.6
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(3,4,6-trimethylammonium-2-propionyl phenyl)-2-thiophenecarboxamides ????23.9
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-[2-(1-hydroxyethyl)-4,6-3,5-dimethylphenyl]-2-thiophenecarboxamides ????26.4
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-the 2-[(dimethylamino) and carbonyl]-4, the 6-3,5-dimethylphenyl)-the 2-thiophenecarboxamides ????14.4
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-2,4-dimethyl-6-[(methoxyl group) and ethanimidoyl] phenyl }-the 2-thiophenecarboxamides ????23.6
3-{[(3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thienyl) carbonyl] amino }-2; 4; 6-trimethylphenyl-N, N-dimethylamino sulphonate ????0.3
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-3-[(cyclopropyl methyl) and the oxygen base]-2; 4, the 6-trimethylphenyl }-the 2-thiophenecarboxamides ????9.4
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2,4,6-trimethylammonium-5-pyrimidyl)-2-thiophenecarboxamides ????2.0
N-(2-ethanoyl-3,4,6-trimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides ????103.8
Compound 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2-cyano group-3; 4, the 6-trimethylphenyl)-the 2-thiophenecarboxamides ??ET AActive *????55.7
N-(2-chloro-4,6-3,5-dimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides ????20.7
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(4,6-diacetyl-3-hydroxyl-2-propyl group phenyl-2-thiophenecarboxamides ????0.1
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2,4-dimethyl-6-[2-(methyl sulphonyl) ethanoyl] phenyl }-the 2-thiophenecarboxamides ????13.7
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2; 4-dimethyl-6-{[methyl (2, the 2-dimethyl propyl) amino] carbonyl } phenyl)-the 2-thiophenecarboxamides ????2.7
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl)-N-[2,4-dimethyl-6-(methyl sulphonyl) phenyl]-2-thiophenecarboxamides ????64.1
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-[2; 4-dimethyl-6-(1,3-oxazoles-2-yl) phenyl]-the 2-thiophenecarboxamides ????17.9
3-{[(4-chloro-5-isoxazolyl) amino] alkylsulfonyl }-N-[2-(2-sulfonyl propyl base)-4, the 6-3,5-dimethylphenyl]-the 2-thiophenecarboxamides ????--
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl)-N-[2,4-dimethyl-6-(sulfonyl propyl base) phenyl]-2-thiophenecarboxamides ????--
3-{[(3,4-dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2-ethanoyl-4,5-methylenedioxyphenyl)-2-thiophenecarboxamides ????0.05
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2,4, the 6-trimethylphenyl)-2-thiophenecarboxamides ????2.4
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-2-(2,4,6-trimethylphenyl ethanoyl) thiophene ????6.4
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(3-methoxycarbonyl-2,4,6-trimethylphenyl)-2-thiophenecarboxamides ????4.7
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2-ethanoyl-4,5-methylenedioxyphenyl)-2-thiophenecarboxamides ????0.15
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2-carbamyl-4,6-3,5-dimethylphenyl)-2-thiophenecarboxamides ????1.04
Compound 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2-carboxyl-4,6-3,5-dimethylphenyl)-2-thiophenecarboxamides ???ET AActive *????0.05
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2-ethyl-4,6-3,5-dimethylphenyl)-2-thiophenecarboxamides ????3.8
3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-[2; 6-dimethyl-4-(1,3-oxazoles-2-yl) phenyl]-the 2-thiophenecarboxamides ????1.1
*With respect to N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylene-dioxy)-6-aminomethyl phenyl) ethanoyl]-ET of thiophene-3-sulphonamide AAntagonistic activity--data do not obtain or suppress to measure with % at 100 μ M
Compound of the present invention is compared with known endothelin antagonists also has higher pharmacokinetic property (seeing the following form 2).As shown in table 2, compound of the present invention is compared with known endothelin antagonists has higher oral administration biaavailability and selectivity.For example; N-(2-ethanoyl-4; the 6-3,5-dimethylphenyl)-3-{[(3; 4 dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-the oral availability of 2-thiophenecarboxamides is 148.1%; and N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylene-dioxy)-6-aminomethyl phenyl) ethanoyl]-the oral availability of thiophene-3-sulphonamide is 43.6%.In addition, N-(2-ethanoyl-4,6-3,5-dimethylphenyl)-3-{[(3,4 dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides is to ET AThe antagonism selectivity ratios of acceptor is to ET BThe antagonism selectivity of acceptor is high by 441000, and N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylene-dioxy)-6-aminomethyl phenyl) ethanoyl]-thiophene-selectivity of 3-sulphonamide in identical test only is 20950.
Table 2 also provides and has confirmed to compare the data that compound of the present invention tolerance in vitro and in vivo all improves with known endothelium peptide receptor antagonists.Referring to embodiment 24.For example, N-(2-ethanoyl-4,6-3,5-dimethylphenyl)-3-{[(3,4 dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides measuring the IC in the vitro test of CP4502C9,2C19 and 3A4 enzyme inhibition 50Value is respectively 7.6,126.3 and 28.0, and N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylene-dioxy)-6-aminomethyl phenyl) ethanoyl]-thiophene-IC of 3-sulphonamide in same test 50Value is respectively 0.03,0.2 and 0.09.In addition; N-(2-ethanoyl-4; the 6-3,5-dimethylphenyl)-3-{[(3; 4 dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides increases mean pulmonary arterial pressure (MPAP) with the dosage of about 1mg/kg in the acute anoxia model to be suppressed 50%; and N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylene-dioxy)-6-aminomethyl phenyl) ethanoyl]-thiophene-3-sulphonamide 50% dosage when suppressing MPAP and increasing in identical test is 2.5mg/kg.Other data also are provided in table 2
Therefore, as in the body and as indicated in the vitro test, compare with known endothelium peptide receptor antagonists, compound of the present invention has higher pharmacokinetic property and tolerance.
Table 2
Compound Oral availability s Selectivity + ??t Eliminate (h)
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylene-dioxy)-6-aminomethyl phenyl) ethanoyl]-thiophene-3-sulphonamide ????43.6 ??20950 ????4.5
N-(2-ethanoyl-4,6-3,5-dimethylphenyl)-3-{ [(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-2-thiophenesulfonamide ????25.1 ??442000 ????4.0
N-(2-m methylsulfonyl ethanoyl-4,6-3,5-dimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenesulfonamide ????16.7 ??66500 ????12.2
N-(2-ethanoyl-4; the 6-3,5-dimethylphenyl)-3-{ [(3,4 dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-2-thiophenecarboxamides ????148.1 ??441000 ????6.0
N-(2-methylsulfonyl-4,6-3,5-dimethylphenyl)-3-{ [(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-2-thiophenesulfonamide ????-- ??456000 ????1.5
N-(2-(2-oxazolyl)-4,6-3,5-dimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenesulfonamide ????-- ??119000 ????5.3
N-(2-cyano group-3; 4, the 6-trimethylphenyl)-3-{ [(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-2-thiophenesulfonamide ????-- ??549800 ????5.1
N-(2-chloro-4,6-3,5-dimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenesulfonamide ????-- ??166000 ????2.6
N-(2-cyano group-3; 4; the 6-trimethylphenyl)-3-{ [(3,4-dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-2-thiophenesulfonamide ????-- ??330000 ????5.3
s% +For ET BIC 50/ for ET AIC 50
Table 2 (continuing)
Compound ???CP450 ????2C9 * ???CP450 ???2C19 * ???CP450 ????3A4 *
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylene-dioxy)-6-aminomethyl phenyl) ethanoyl]-thiophene-3-sulphonamide ????0.03 ????0.2 ????0.09
N-(2-ethanoyl-4,6-3,5-dimethylphenyl)-3-{ [(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-2-thiophenesulfonamide ????1.67 ????48.8 ????3.3
N-(2-methylsulfonyl ethanoyl-4,6-3,5-dimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenesulfonamide ????5.1 ????50.6 ????4.0
N-(2-ethanoyl-4; the 6-3,5-dimethylphenyl)-3-{ [(3,4 dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-2-thiophenecarboxamides ????7.6 ????126.3 ????28.0
N-(2-methylsulfonyl-4,6-3,5-dimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenesulfonamide ????5.3 ????6.2 ????13.7
N-(2-(2-oxazolyl)-4,6-3,5-dimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenesulfonamide ????-- ????-- ?????--
N-(2-cyano group-3; 4, the 6-trimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenesulfonamide ????0.77 ????13.53 ????1.44
N-(2-chloro-4,6-3,5-dimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenesulfonamide ????0.56 ????4.60 ????3.86
N-(2-cyano group-3; 4; the 6-trimethylphenyl)-and 3-{[(3,4-dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenesulfonamide ????2.38 ????14.36 ????3.30
*IC 50Value (μ M).
Table 2 (continuing)
Compound ??C max(μg) Acute anoxia #
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylene-dioxy)-6-aminomethyl phenyl) ethanoyl]-thiophene-3-sulphonamide ????133.2 ????2.5
N-(2-ethanoyl-4,6-3,5-dimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenesulfonamide ????58.8 ????1
N-(2-methylsulfonyl ethanoyl-4,6-3,5-dimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenesulfonamide ????37.3 ????＞5
N-(2-ethanoyl-4; the 6-3,5-dimethylphenyl)-3-{ [(3,4 dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-2-thiophenecarboxamides ????157.2 ????1
N-(2-methylsulfonyl-4,6-3,5-dimethylphenyl)-3-{ [(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-2-thiophenesulfonamide ????10.3 ????--
N-(2-(2-oxazolyl)-4,6-3,5-dimethylphenyl)-3-{ [(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-2-thiophenesulfonamide ????66 ????--
N-(2-cyano group-3; 4, the 6-trimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenesulfonamide ????45.7 ????1-5
N-(2-chloro-4,6-3,5-dimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenesulfonamide ????49.5 ????--
N-(2-cyano group-3; 4; the 6-trimethylphenyl)-3-{ [(3,4-dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-2-thiophenesulfonamide ????85.8 ????1-5
#In vivo in the model, mean pulmonary arterial pressure is increased dosage (mg/kg) B when producing 50% restraining effect, the preparation of compound
Some preparation methods with required active above-mentioned and other compound are shown among the embodiment.Wherein the compound of clear and definite its synthesis method can not utilize one or more methods that describe in detail among the embodiment to modify through conventional, suitably substitutes and can synthesize with handy reagent.
Many compounds of describing herein are 3-sulfamyl-2-aromatic yl aminocarbonyl thiophene derivants.Generally, these compounds can prepare with the aniline that is substituted or is unsubstituted by the suitable 3-sulfamyl thienyl carboxylic acid of coupling.
3-sulfamyl thienyl carboxylic acid can prepare by the whole bag of tricks well known by persons skilled in the art.Generally, most of synthesis methods relate to carbonyl alkoxy thiophene base SULPHURYL CHLORIDE and the condensation reaction of amido isoxazole in anhydrous pyridine or tetrahydrofuran (THF) (THF) and sodium hydride.Form needed acid with posthydrolysis carbonyl alkoxyl group.SULPHURYL CHLORIDE and amido isoxazole can commercially availablely obtain or according to method described in the embodiment or adopt additive method well known by persons skilled in the art synthetic (referring to for example the 4th, 659,369,4,861,366 and 4,753, No. 672 United States Patent (USP)s).
For example, thienyl sulphonyl chlorine can prepare by the following method.For example with bromine or N-bromosuccinimide reaction, at 2 bromination 3-sulfamyl thiophene precursors.Metal-halogen and lithium alkylide such as n-Butyl Lithium exchange subsequently, again with carbon dioxide reaction, form needed acid thus.Other method is, the sulphur trioxide reaction with in the sulfuric acid for example makes 2-thienyl carboxylic acid derivative 3 sulfonation.The sulfonic acid of gained is converted into SULPHURYL CHLORIDE (with phosphorus pentachloride, phosphorus trichloride, phosphoryl chloride, thionyl chloride or oxalyl chloride reaction), with suitable amine reaction, forms needed sulfamyl thienyl carboxylic acid derivative then.Intermediate sulfonyl chloride also can be directly reaction by thienyl carboxylic acid derivative and chlorsulfonic acid prepare.
The preparation method of N-(alkyl isoxazolyl) sulphonamide can use or not use catalyzer 4-(dimethyl aminopyridine) condensation by amido isoxazole and SULPHURYL CHLORIDE in anhydrous pyrrole forms sediment.N-(3,4-dimethyl-5-isoxazolyl) sulphonamide and N-(4,5-dimethyl-3-isoxazolyl) sulphonamide then can be prepared by corresponding amino dimethyl isoxazole, as 5-amino-3, and the 4-dimethyl isoxazole.For example, N-(3,4-dimethyl-5-isoxazolyl)-2-(carboxymethoxyl) thiophene-3-sulphonamide is that the 4-dimethyl isoxazole prepares in anhydrous pyridine by 2-methoxycarbonyl thiophene-3-SULPHURYL CHLORIDE and 5-amino-3.
The preparation method of N-(4-halogen isoxazolyl) sulphonamide can use sodium hydride as alkali by amino-4-halogen isoxzzole and SULPHURYL CHLORIDE in THE, carries out condensation.For example, N-(4-bromo-3-methyl-5-isoxazolyl) thiophene-2-sulphonamide is to be prepared in THF and sodium hydride by 5-amino-4-bromo-3-methyl isoxzzole and thiophene-2-SULPHURYL CHLORIDE.
These sulphonamide also can in pyridine, use or not use 4-dimethylaminopyridine (DMAP) preparation of catalytic amount by corresponding SULPHURYL CHLORIDE and amido isoxazole.In some cases, can obtain the disulfonyl based compound is main or unique product.This disulfonyl product uses aqueous sodium hydroxide solution and suitable co-solvents easily, as methyl alcohol or tetrahydrofuran (THF), on room temperature, is hydrolyzed into sulphonamide usually.
Substituted aniline is by synthesizing with for example nitric acid and vitriolic mixture or the nitrated suitable precursor substituted benzene of nitronium tetrafluoroborate.With for example aromatic nitro compound of zinc powder, catalytic hydrogenation, tin protochloride or any other method known to those skilled in the art reduction gained, obtain needed aniline.
The coupling of thienyl carboxylic acid and aniline can followingly be carried out: acid is converted into corresponding acylimidazole (for example with the carbonyl dimidazoles reaction) or chloride of acid (for example with oxalyl chloride or thionyl chloride reaction); with aniline reaction, form desirable aromatic aminocarbonyl thiophene compound then.
Compounds more described herein are 3-sulfamyl-2-benzylamino carbonyl thiophene derivants.When these compounds of preparation, the aniline among the above-mentioned preparation method can be replaced with benzylamine.Suitable benzylamine can followingly synthesize: corresponding benzyl halide reacts with trinitride, handles by for example catalytic hydrogenation or with trialkyl or triaryl phosphine then and reduces the benzyl azide thing of gained.
Other compound described herein is 3-sulfamyl-2-aryl acetyl thiophene derivative.These compounds can form by add suitable benzylmagnesium chloride in 3-sulfamyl-2-Thiophene Carboxylic Acid derivative such as N-methyl-N-methoxyamide.Described acid amides can be prepared as follows: make acid and carbonyl dimidazoles reaction, then with N-methyl-N-methoxyl group amine reaction.
Some compound described here can prepare with the method for describing in the following synthetic route 1: R wherein 1Be halogen or low alkyl group, wherein preferably chlorine and methyl.
For the compound of formula A, R 60Form the carboxylic acid or derivatives thereof with CO.In the case, R 60Be preferably OR 40, R wherein 40Be low alkyl group or alkoxyalkyl, preferable methyl or methoxymethyl are perhaps with corresponding to other groups of desirable chemistry.
For the compound of formula C or D, R 60Be OR 40, halogen or with corresponding to other carboxylic acid activating groups of desirable chemical conversion, wherein chlorine especially preferably.
For the compound of formula E, Ar can be any fragrance or heteroaryl ring, wherein preferably benzene and pyrimidine.
The prodrug that is fit to the compound of administration human body also can and prepare according to the known method design of art technology with other derivatives (referring to for example: Nogrady (1985) medicinal chemistry, biochemical spy opinion, Oxford University Press, New York (Medicinal Chemistry A Biochemical Approach,Oxford University Press, New York, 388-392 page or leaf).
The illustrated compound of this paper is synthetic, and in vitro test its activity of test, and some carries out in living Animal Models.The analysis of being undertaken by NMR (Nuclear Magnetic Resonance) spectrum (NMR), mass spectrum, infrared spectra and high performance liquid chromatography shows that the structure of institute's synthetic compound is consistent with the due structure of these compounds, and common purity is at least about 98%.All compounds that this paper exemplified or illustrated all have the endothelin antagonists activity.C, the bioactive assessment of compound
Can adopt standard physiology, pharmacy and biochemical method to come test compounds, with the compound of identifying that those have any endothelium peptide biological activity or have interference or suppress the ability of endothelium peptide.Compound with external activity, compete the compound that combines endothelium peptide acceptor as having the ability in conjunction with endothelium peptide acceptor or with one or more endothelium peptides, can be used for separating in the method and the narrow spectrum method of explanation endothelium peptide acceptor of endothelium peptide acceptor, and can be the drug candidate that is used for the treatment of by in the method for endothelin-mediated disorder.
Therefore, except the compound that the present invention offers some clarification on, other also can use this type of sieve method to differentiate for the preferred formula I and the II compound of endothelin antagonists or agonist. 1, adjusts the discriminating of the active compound of endothelium peptide
Test compounds is adjusted the active ability of endothelium peptide-1.Those skilled in the art are known to be had many analytical methods can assess compound to adjust the active ability of endothelium peptide (referring to, the 5th, 114, No. 918 United States Patent (USP)s of people such as Ishikawa for example; EP A10436189, BANYU PHARMA-CEUTICAL CO., LTD. (on October 7th, 1991); People such as Borges (1989) Eur.J. Pharm.165: 223-230; People such as Filep (1991) Biochem.Biophys.Res.Commum. 177: 171-176).In vitro tests can be proofreaied and correct (referring to for example: the 5th, 114, No. 918 United States Patent (USP)s of people such as Ishikawa by test in vivo; EP A10436189, BANYUPHARMACEUTICAL CO., LTD. (on October 7th, 1991)), and analyze pharmaceutical activity thus.These analytical methods have been illustrated among this paper embodiment, and comprise from it handling and express ET at cell surface from accepting genetic engineering AOr ET BET in the cell strain of acceptor on the isolating film AAnd ET BThe acceptor bonded ability that is at war with.
The character of potential antagonist can adopt particular organization, as mouse portal vein and aorta, mouse uterus, tracheae and vas deferens, analyze its with the variation that in vivo suppresses the active ability that the endothelium peptide brought out (referring to for example: R.Borges, H.Von Grafenstein, and D.E.Knight, " tissue selectivity of endothelium peptide " (Tissue selectivity of endothelin) Eur.J.Pharmacol.165:223-230 (1989)).Adopt the animal model of hypertension rat, ddy small white mouse or other approvals, test its in vivo as the ability of endothelin antagonists (referring to people such as Kaltenbronn, (1990) J.Mde.Chem.33: 838-845, also referring to the 5th, 114, No. 918 United States Patent (USP)s of people such as Ishikawa; And EP A10436189, BANYU PHARMACEUTICAL CO., LTD. (on October 7th, 1991); Also referring to people such as Bolger (1983) J.Pharmacol.Exp. Ther.225: 291-309).Adopt this type of zooperal result can assess drug effectiveness and measure medicine effective dose.Potential agonist also can use the known external and in vivo analytical method assessment of those skilled in the art.
Endothelium peptide activity can by test compound stimulate the ability of the mouse thoracic aorta contraction of separations identify (people (1989) such as Borges, " tissue selectivity of endothelium peptide " (Tissue selectivity ofendothelin), Eur.J.Pharmacol.165: 223-230.When analyzing, remove endothelium, be cut into link, in tissue bath, be placed under the tension force, under the existence of test compound, handle with the endothelium peptide.The tension variation that record endothelium peptide is brought out.Produce dose response curve, the data of the relative inhibition effectiveness of test compound is provided.Its hetero-organization comprises heart, skeletal muscle, kidney, uterus, tracheae and vas deferens, all can be used to assess the effect of special test compound to tissue contracts.
Endothelium peptide isoform specificity antagonist can be disturbed the endothelium peptide and be expressed the tissue of different endothelium peptide-receptor subtypes or the combination of cell by test compound, or (the people (1991) such as Takayanagi that disturbs the ability of the biological effect of endothelium peptide or endothelium peptide isoform to identify Reg.Pep.32: 23-37; People such as Panek (1992) Biochem.Biophys.Res.Commun.183: 556-571).For example, ET BExpression of receptor may be regulated prostacyclin and derived from the release of the relaxation factor of endothelium peptide (people (1988) such as De Nucci in vascular endothelial cell Proc.Natl.Acad.Sci.USA 85: 9797).ET AAcceptor then do not see through cultivate, express ET BIn the endotheliocyte of acceptor.
The combination of analysis of compounds or inhibition endothelium peptide and ET BAcceptor in conjunction with the time, be to be undertaken, that is measure by the main metabolite, 6-ketone group PGF stablized that discharges in the bovine aortic endothelial cells through cultivating by measuring the restraining effect that prostacyclin that endothelium peptide-1 is regulated discharges 1 α(for example see: people such as Filep (1991) Biochem.And Biophys Res.Commun.177: 171-176).Therefore, the assessment compound is during to the relative affinity of different endothelium peptide acceptors, can adopt with the different tissue of receptor subtype and measure the inhibition dose-response curve.
When adopting these analytical methods, but analysis of compounds is to ET AAcceptor and ET BThe relative affinity of acceptor.Select and have required character, as compound the single-minded inhibition of endothelium peptide-1 keying action.Through select have required active compound can be used for the treatment, and adopt above-mentioned assess its in vivo the analytical method of validity test this kind purposes (referring to for example the 5th, 248, No. 807 United States Patent (USP)s; The 5th, 240, No. 910 United States Patent (USP)s; The 5th, 198, No. 548 United States Patent (USP)s; The 5th, 187, No. 195 United States Patent (USP)s; The 5th, 082, No. 838 United States Patent (USP)s; The 5th, 230, No. 999 United States Patent (USP)s; Disclosed the 2nd, 067,888 and No. 2071193 Canadian patent application; The application of disclosed the 2nd, 259, No. 450 Britain; Disclosed international pct application WO 93/08799; People such as Benigi (1993) Kidney Internatioal44:440-444; And people (1993) such as Nirei Life Sciences52:1869-1874).Have external activity and the compound relevant with validity in the body promptly can be formulated into suitable pharmaceutical compositions, and with being therapeutical agent.
These compounds also can be used for identifying and separate endothelium peptide specificity acceptor, and help to design more potent endothelin antagonists or agonist or to the more narrow spectrum compound of specific endothelium peptide acceptor. 2, the separation of endothelium peptide acceptor
This paper provides a kind of method of identifying endothelium peptide acceptor.When operation present method, one or more compounds are connected on the carrier, and are used for the affinity method of purification of acceptor.When selection has specific narrow spectrum compound, can identify the hypotype of different ET acceptors.
One or more compounds can be connected to suitable resin, and as the Affi-gel, it is to carry out covalently bound with the method for these resins or other modes are connected (referring to people such as Schvartz (1990) according to connection endothelium peptide well known by persons skilled in the art Endocrinology 126: 3218-3222).The compound that connects then can be those to ET AOr ET BAcceptor or other receptor subtypes are narrow spectrum compound.
Resin is earlier with the suitable buffer reagent balance under physiological pH (7 to 8) usually.Get the composition that dissolves acceptor and the compound mixed with resin to be connected that contain from particular organization, and the selective elution acceptor.Test receptors bind endothelium peptide is with the situation of merit peptide or analogue or utilize the method for other identification of protein and identification feature to identify acceptor.The preparation of acceptor, resin and elution method can be undertaken by revising standard program well known by persons skilled in the art (referring to for example: people such as Schvartz (1990) Endocrinology 126: 3218-3222).
This paper provides the additive method of explanation acceptor type according to the differential avidity of acceptor and any compound.This paper is illustrated to be used to measure specific compound any analytical method of the avidity of endothelium peptide acceptor be can be used for according to acceptor the avidity of specific compound that this paper provides being offered an explanation receptor subtype.Particularly, when measuring unknown acceptor and providing the binding affinity of the compound that known its avidity to a kind of acceptor is higher than another kind of acceptor, can identify that it is ET to this paper AOr ET BAcceptor.These priorities interact and are applicable to that mensuration can adopt the specified disease of the compounds for treating that makes described herein.For example, to ET AReceptor affinity is high and to ET BReceptor affinity compound low or that do not have can be used as the drug candidate of hypertension agent; And preferential and ET BThe compound of acceptor interaction then is applicable to the drug candidate into anti-asthma agent.The allotment of D, composition and administration
The present invention also provides the preparation of sulphonamide.Described preparation is the composition that is used for acceptable derivates, particularly its salt on the pharmacology of administration sulfonamide compounds described herein.Owing to compare with neutral form, the stability of salt, particularly sodium salt is high, so be particularly suitable for oral or non-through gastrointestinal administration.These compositions comprise solution, suspension, tablet, dispersible tablet, pill, capsule, powder, sustained release preparation or any other dosage forms.Said composition is preferably pill or tablet.The method of making tablet, capsule and other these preparations is known (referring to for example: Ansel, H.C (1985) Introduction to Pharma-ceutical DosageForms, the 4th edition, 126-163 page or leaf) for those skilled in the art.
In described preparation, acceptable derivates mixes with suitable pharmaceutical carrier or supporting agent on one or more pharmacology of effective concentration.Preferably, before preparation, sulfonamide compounds is derived as mentioned above to corresponding salt, is preferably sodium salt.The concentration of compound salt should make the amount that discharges when administration can effectively improve the symptom of the disease that the endothelium peptide regulated in the preparation.Generally, composition is mixed with the form of single dose administration.When compositions formulated, with compound dissolution, suspend, be dispersed in the selected carrier or with described carrier and mix, the weight part of this compound should make its concentration be enough to alleviate or improve the illness of being treated.The pharmaceutical carrier or the supporting agent that are suitable for the administration The compounds of this invention comprise any carrier that is applicable to concrete form of medication well known by persons skilled in the art.In addition, The compounds of this invention can be formulated in the composition as active constituents of medicine separately, perhaps mixes with other activeconstituents.The liposome suspensoid, comprise tissue target to liposome, also be suitable for as acceptable carrier on the pharmacology.They can prepare according to method known to those skilled in the art.For example, Liposomal agents can be as the 4th, 522, and No. 811 United States Patent (USP) prepares.
Salt, the active compound amount in the acceptable carrier on pharmacology that is preferably sodium-salt form should be enough to the patient who is treated is produced useful therapeutic action, but not have side reaction.Treatment effective concentration can be determined by test compounds in the system in vitro and in vivo (referring to for example: the 5th, 114, No. 918 United States Patent (USP)s of people such as Ishikawa empirically; EP A1 0436189, BanyuPharmaceutical Co., Ltd. (on October 7th, 1991); People such as Borges (1989) Eur.J. Pharm.165: 223-230; People such as Filep (1991) Biochem.Biophys.Res.Commun. 177: 171-176), extrapolate thus then and obtain being used for people's dosage.
The concentration of active compound sodium salt depends on absorption, inactivation and the discharge rate of this active compound, physicochemical characteristic, dosage regimen, dosage and the other factors well known by persons skilled in the art of this compound in the pharmaceutical composition.For example, the amount of institute's administration should be enough to treat hypertensive symptom.Wish that the significant quantity of treatment endothelin-mediated disorder is higher than the amount of the sulfonamide compounds of drug treatment infectation of bacteria.
Generally, the treatment effective dose should produce the activeconstituents serum-concentration of about 0.1ng/ml to about 50-100 μ g/ml.Pharmaceutical composition provides the dosage of about 0.001-2000mg compound/kg body weight/day usually.Drug prepared dosage unit formulation can provide about 1-1000mg, the preferred combination/dosage unit formulation of about 10-500mg primary activity component or basal component.
Active ingredient is administration once, perhaps is divided into a plurality of low dose of administrations at a certain time interval.It should be understood that precise therapeutic dosage amount and time length change with disease to be treated, and can use known testing scheme in body or the extrapolation of vitro test data determine empirically.It should be noted that concentration and dose value also can change according to the severity of the illness of waiting to alleviate.Further be understood that, for any special patient, concrete dosage regimen should be according to individuality required and administration people or monitor that the people's of administration composition professional judgement regulates in time, and above-mentioned concentration range only is exemplary, is not used for limiting the scope or actual use of the present composition.
Acceptable derivates comprises acid, salt, ester, hydrate, solvate and prodrug form on the preferred pharmacology.Selected derivative should be more stable than corresponding neutral compound.Preferred salt comprises an alkali metal salt, and particularly sodium salt such as but not limited to sodium hydrogen phosphate and sodium salt, most preferably is sodium salt.
Therefore, acceptable derivates mixes mutually with the pharmaceutical carrier that is suitable for whole body, fixed point or topical on one or more the present invention's of effective concentration or amount compound or its pharmacology, forms pharmaceutical composition thus.The disease by the adjusting of endothelium peptide of institute's desire treatment should effectively be alleviated or treat to the compound amount that comprises in the composition.The concentration of active compound depends on the absorption, inactivation, discharge rate, dosage regimen, dosage of this active compound, concrete preparation and other factors well known by persons skilled in the art in the composition.
The present composition can be according to the disease of being treated by the suitable way administration, and this comprises oral, non-through gi tract, rectum, fixed point and topical.For example, when treatment ophthalmic diseases such as glaucoma, can be made into the formulation of intraocular and intravitreal injection administration.When oral administration, preferred capsule and tablet.During through gastrointestinal administration, preferred aforesaid non-through the restorative lyophilized powder.Compound can be liquid, semiliquid or solid dosage, and prepares in the mode that is suitable for each route of administration.Preferred administering mode comprises non-through gi tract and oral administration.
Be used for non-through gi tract, can comprise following any material through intracutaneous, solution or suspension subcutaneous or topical: sterile diluent, as water for injection, salt brine solution, mixing oil, polyoxyethylene glycol, glycerine, propylene glycol or other synthetic; Antiseptic-germicide is as benzylalcohol and methyl p-hydroxybenzoate; Oxidation inhibitor is as xitix and sodium bisulfite; Sequestrant is as ethylenediamine tetraacetic acid (EDTA) (EDTA); Buffer reagent is as acetate, Citrate trianion and phosphoric acid salt; And the reagent that is used to regulate ionic strength, as sodium-chlor or glucose.Non-preparation through gastrointestinal administration can be enclosed in ampoule, disposable syringe or the list of being made by glass, plastics or other suitable material or multiple doses phial.
When the solubleness of compound is not enough, can adopt the method for solubilize compound.These methods are well known by persons skilled in the art, and include but not limited to: use cosolvent, as dimethyl sulfoxide (DMSO) (DMSO), use tensio-active agent, as tween, or be dissolved in the sodium bicarbonate aqueous solution.The derivative of compound as the salt of compound or the prodrug of compound, also can be used for allocating drug composition effective.
When mixing or add the sodium salt of sulfonamide compounds, formed mixture can be solution, suspension, emulsion, or the like.The form of formed mixture is decided according to many factors, comprising: the mode of administration of plan and the compound dense degree of separating in specific support or supporting agent.Effective concentration is enough to improve the symptom of disease to be treated, pathology or illness, and can be by the experiment decision.
The preparation that is used to deliver medicine to humans and animals can be the dosage unit formulation, for example tablet, capsule, pill, powder agent, granule, aseptic injectable solution agent or suspensoid and oral liquid or suspensoid, oil-aqueous emulsion, they all comprise acceptable salt on the compound of appropriate amount, particularly its pharmacology, are preferably sodium salt.The compound of therapeutic activity and derivative thereof are mixed with dosage unit formulation or many doses formulation and administration usually on the pharmacology.Dosage unit formulation described herein is meant the humans and animals patient and the independent unit independently physically of packing of being applicable to well known by persons skilled in the art.Each dosage unit comprises therapeutical active compound and needed pharmaceutical carrier, supporting agent or the thinner of predetermined amount, and the amount of described active compound is enough to produce desirable result of treatment.The example of dosage unit formulation comprises ampoule and syringe, the tablet or the capsule of packing separately.The dosage unit formulation can its part or many parts of administrations.Many doses formulation is meant a plurality of same unit dosage formulations that are packaged in the single container, and with independently dosage unit formulation administration.Many doses formulation comprises phial, tablet bottle or capsule or pint or gallon bottle.Therefore, many doses formulation is a plurality of dosage units of not packing separately.
Composition of the present invention can comprise activeconstituents: thinner, as lactose, sucrose, dicalcium phosphate or carboxymethyl cellulose; Lubricant is as Magnesium Stearate, calcium stearate and talcum; And tackiness agent, as starch, natural gum such as kordofan gum, glucose, molasses, polyvinylpyrrolidone, Mierocrystalline cellulose and its derivative, povidone, crospovidone and other tackiness agent well known by persons skilled in the art.Pharmaceutical composition that can the liquid administration can for example prepare by the following method: dissolving in carrier, disperse or mix aforesaid active compound and optional pharmaceutical adjuvant, described carrier for example is water, salt solution, D/W, glycerine, ethylene glycol, ethanol etc., forms solution or suspension thus.If desired, the pharmaceutical composition for the treatment of administration also can comprise a spot of non-toxic auxiliary substances, as wetting agent, emulsifying agent or solubilizing agent, pH buffer reagent etc., as acetate, Trisodium Citrate, cyclodextrin derivative, Span-20, trolamine sodium acetate, triethanolamine oleate and other these reagent.The practical methods for preparing these formulations is known or conspicuous for those skilled in the art; For example, referring to Remington ' sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., the 15th edition, 1975.Composition or the preparation for the treatment of administration comprise a certain amount of active compound at any time, and this amount should be enough to alleviate the patient's that treats symptom.
Can prepare and comprise the 0.005%-100% activeconstituents, all the other are the formulation or the composition of non-toxicity carrier.For oral administration, sneak into any conventional vehicle that uses, as seminose, lactose, starch, Magnesium Stearate, talcum, derivatived cellulose, croscarmellose sodium, glucose, sucrose, magnesiumcarbonate or the soluble saccharin of pharmaceutical grade, form acceptable non-toxic composition on the pharmacology thus.These compositions comprise solution, suspensoid, tablet, capsule, powder agent and sustained release preparation, such as but not limited to the drug delivery system and the polymkeric substance biodegradable and that biophase is suitable of implant and micro encapsulation, as collagen, ethylene vinyl acetate, polyanhydride, polyglycolic acid, poe, poly(lactic acid) etc.The method for preparing these preparations is known for those skilled in the art.Composition of the present invention can comprise the 0.001-100% activeconstituents, and preferred 0.1-85% is generally 75-95%.
The salt of active compound, particular certain cancers can be mixed with carrier, and this carrier protection compound is avoided eliminating in body fast, for example time release formulation or dressing.
Described preparation can comprise other active compound, to obtain desirable performance combination.Acceptable salt and derivative can advantageously be used for the treatment of or prevent purpose, for example β-adrenergic blocker (for example atenolol USP 23) on the present invention's formula I compound or its pharmacology with other medicament co-administered that is used for the treatment of one or more above-mentioned diseases or illness known in the art; calcium channel blocker (as nifedipine); angiotensin-converting enzyme (ACE) inhibitor (as lisinopril); diuretic(s) (as Furosemide or hydrochlorothiazide); endothelin-converting enzyme (ECE) inhibitor (for example phosphoramidon); neutral endopeptidase (NEP) inhibitor; the HMGCoA reductase inhibitor; nitric oxide donor; oxidation inhibitor; vasodilator; dopamine agonist; neuroprotective; steroidal; beta-2-agonists; anti-coagulant; or thrombolytic agent.It should be understood that these combined therapies have constituted another aspect of the present composition and methods of treatment.1, oral Preparation
Oral administered dosage form can be solid, gel or liquid preparation.Solid dosage has tablet, capsule, granule, bulk powder agent.The type of oral tablet comprises the chewing lozenge and the tablet of compression, and they can be casing, sugar-coat or film-coated.Capsule can be hard or soft gelatin capsule, and particle and powder agent can make up with non-effervesce or effervesce formulation with other composition well known by persons skilled in the art and provide.
In certain embodiments, preparation is a solid dosage, is preferably capsule or tablet.Tablet, pill, capsule, lozenge etc. can comprise following any composition or kin compound: tackiness agent, thinner, disintegrating agent, lubricant, glidant, sweeting agent and seasonings.
The example of tackiness agent comprises Microcrystalline Cellulose, tragacanth gum, glucose solution, mucialga of arabic gummy, gelatin solution, sucrose and starch paste.Lubricant comprises talcum, starch, Magnesium Stearate or calcium stearate, spores of Wolf's claw clubmoss and stearic acid.Thinner comprises lactose, sucrose, starch, kaolin, salt, seminose and Lin Suanergai.Glidant includes but not limited to colloid silica.Disintegrating agent comprises croscarmellose sodium, primojel, alginic acid, W-Gum, yam starch, wilkinite, methylcellulose gum, agar and carboxymethyl cellulose.Tinting material comprises any water-soluble FD and C dyestuff, their mixture through approval; And be suspended in water-insoluble FD and C dyestuff in the hydrated alumina.Sweeting agent comprises sucrose, lactose, seminose and artificial sweetner, as Crystallose and asccharin; And any spray-dired virtue flavor agent.Seasonings comprises natural flavouring that extracts and the synthetic mixture that can produce the compound of pleasant sensation from plant such as fruit, such as but not limited to foreign peppermint and wintergreen oil.Wetting agent comprises propylene glycol monostearate, dehydrated sorbitol mono-fatty acid ester, Diethylene Glycol mono-laurate and polyoxyethylene lauryl ether.Emetic dressing comprises lipid acid, fat, wax, shellac, amino shellac and Cellacefate.Film coating comprises Natvosol, Xylo-Mucine, Macrogol 4000 and Cellacefate.
Oral administration if desired, the salt of compound can be formulated in the composition, to prevent the sour environment of gastric juice.For example, composition can be formulated in the enteric coating, and this dressing can keep its integrity under one's belt, and in intestines release of active compounds.Composition also can be mixed with and antacid or the combination of other analogous components.
If the dosage unit formulation is a capsule, except that the material of above type, it also can comprise liquid vehicle such as fatty oil.In addition, the dosage unit formulation can comprise the various materials that improve the physical form of this dosage unit formulation, for example sugar-coat and other enteric agents.Compound can also be as the administration of assigning to of the one-tenth in elixir, suspensoid, syrup, wafer, spray agent (sprinkle), the chewing gum agent etc.Remove the active ingredient beyond the region of objective existence, syrup also can comprise as the sucrose of sweeting agent and some sanitas, dyestuff, tinting material and seasonings.
Active substance also can mix mutually with other active substance that does not damage desired effect, perhaps mixes with the material such as antacid, H2 blocker and the diuretic(s) that strengthen desired effect.For example, if The compounds of this invention is used for the treatment of asthma or hypertension, it can use with other bronchodilators and antihypertensive drug respectively.Activeconstituents is described herein compound or its salt.The activeconstituents that also can comprise greater concn, the about 98 weight % of as many as.
Acceptable carrier is tackiness agent, lubricant, thinner, disintegrating agent, tinting material, seasonings and sweeting agent on the pharmacology that comprises in the tablet.Because its casing, the casing sheet can resist the effect of hydrochloric acid in gastric juice, and dissolving or disintegration in neutral or alkaline enteron aisle.Coated tablet is a compressed tablets, and acceptable material on the pharmacology of different layers is wherein arranged.Thin membrane coated tablet is the compressed tablets that comes dressing with polymkeric substance or other suitable dressing.Repeatedly compressed tablets is to use said medicine to go up acceptable material and suppresses the compressed tablets that circulation is made more than once.Tinting material also can be used in the above-mentioned formulation.Seasonings and sweeting agent are used for compressed tablets, sugar coated tablet, repeatedly compressed tablets and chewing tablet.Seasonings and sweeting agent are used in particular in chewing tablet and the lozenge.
The effervescent formulation that liquid oral dosage form comprises the aqueous solution, emulsion, suspensoid, restored the solution that forms and/or suspensoid and formed by the effervescent granule recovery by non-effervescent granule.The aqueous solution for example comprises elixir and syrup.Emulsion can be oil-in-water or water-in-oil-type.
Elixir is clarifying, sweet water alcohol formulations.In the elixir on the used pharmacology acceptable carrier comprise solvent.Syrup is dense sugar aqueous solution, sucrose for example, and can comprise sanitas.Emulsion is the system of two phases, and wherein a kind of liquid is dispersed in the another kind of liquid with coccoid.The aqueous liquid of acceptable carrier right and wrong, emulsifying agent and sanitas on the used pharmacology in the emulsion.But suspensoid uses the suspension agent and the sanitas of technology on the pharmacology.Parked becomes that acceptable carrier comprises thinner, sweeting agent and wetting agent on the pharmacology used in the non-effervescent granule of liquid oral dosage form.Parked becomes that acceptable carrier includes organic additive and carbon dioxide source on the pharmacology used in the effervescent granule of liquid oral dosage form.In above all formulations, all use tinting material and seasonings.
Solvent comprises glycerine, sorbyl alcohol, ethanol and syrup.Examples of preservatives comprises glycerine, Tegosept M and propylben, benzoic acids additive, Sodium Benzoate and alcohol.Non-aqueous liquid used in the emulsion comprises mineral oil and Oleum Gossypii semen.The example of emulsifying agent comprises gelatin, kordofan gum, tragacanth gum, wilkinite and tensio-active agent, as polyoxyethylene sorbitan monooleate.Suspension agent comprises Xylo-Mucine, pectin, tragacanth gum, V word glue and kordofan gum.Thinner comprises lactose and sucrose.Sweeting agent comprises sucrose, syrup, glycerine and artificial sweetner, as Crystallose and asccharin.Wetting agent comprises propylene glycol monostearate, polyoxyethylene-sorbitan mono-oleate, Diethylene Glycol mono-laurate and polyoxyethylene lauryl ether.Organic additive comprises citric acid and tartrate.Carbon dioxide source comprises sodium bicarbonate and yellow soda ash.Tinting material comprises any water-soluble FD and C dyestuff and their mixture through approval.Seasonings comprises natural flavouring that extracts and the synthetic mixture that can produce the compound of pleasant sensation from plant such as fruit.
For solid dosage, solution in for example propylene carbonate, vegetables oil or triglyceride level and the preferred encapsulate of suspension are in gelatine capsule.These solution, its preparation method and encapsulation methods see the 4th, 328,245,4,409,239 and 4,410, and No. 545 United States Patent (USP)s.For liquid dosage form, the solution in polyoxyethylene glycol for example, acceptable liquid vehicle such as water dilute on the pharmacology of available q.s, with easy metering administration.
In addition, liquid or semisolid oral formulations prepare by the following method: with the dissolving of active compound or salt or be dispersed in vegetables oil, polyvalent alcohol, triglyceride level, propylene glycol ester (for example propylene carbonate) and other these carriers, then with these solution encapsulates in hard or soft gelatin capsule shell.Other useful preparation comprises Re 28,819 and 4,358, described in No. 603 United States Patent (USP)s.
In one embodiment, preparation is a solid dosage, is preferably capsule or tablet.In preferred embodiments, preparation is a solid dosage, be preferably capsule or tablet, it comprises 10-100 weight %, preferred 50-95 weight %, more preferably 75-85 weight %, most preferably one or more sulphonamide or the sulfonamide of 80-85 weight %, be preferably the sodium hydrogen phosphate salt or the sodium salt of one or more sulfonamide compoundss of formula I, more preferably sodium salt; Thinner or the tackiness agent of about 0-25%, preferred 8-15%, for example lactose or Microcrystalline Cellulose; The disintegrating agent of about 0-10%, preferred 0-7%, for example through the starch or the cellulose polymer compound of modification, croscarmellose sodium particularly, (croscarmellose sodium NF can be from FMCCroporation as croscarmellose sodium, Philadelphia, PA buys with the AC-DI-SOL trade(brand)name) or primojel; And the lubricant of 0-2%, for example Magnesium Stearate, talcum and calcium stearate.Disintegrating agent, for example croscarmellose sodium or primojel can make the quick disintegration of cellulose matrix, release of active agent immediately after the dressing polymer dissolution.In all embodiments, the accurate amount of activeconstituents and ancillary component can be measured empirically, and changes with route of administration and the disease of being treated.
In exemplary, preparation is a capsule, and it comprises about 50-100%, preferred 70-90%, more preferably 80-90%, one or more sodium salts of the sulfonamide compounds of one or more formulas I of 83% most preferably; About 0-15%, preferred 11% thinner or tackiness agent, for example lactose or Microcrystalline Cellulose; About 0-10%, preferred 5% disintegrating agent, for example croscarmellose sodium or primojel; And about 0-5, preferred about 1% lubricant, for example Magnesium Stearate.With the solid dosage of tablet administration also within this scope.
In exemplary preferred embodiment, preparation is a capsule, and it comprises one or more sodium salts of one or more sulfonamide compoundss of 83%; 11% Microcrystalline Cellulose; 5% disintegrating agent, for example croscarmellose sodium or primojel; And 1% Magnesium Stearate.
Above-mentioned embodiment also can be mixed with tablet, and randomly carries out dressing.Tablet comprises above-mentioned composition.
In all embodiments, tablet and capsule can carry out dressing as known in the art, to improve or to keep the dissolving of active ingredient.For example, tablet can come dressing with enteric coating such as salol, wax and the Cellacefate of routine.2, injection, solution and emulsion
Parenteral administration generally includes injection, subcutaneous, intramuscular or intravenous administration, also within the scope of the invention.Injection can be made into conventionally form, as liquor or suspensoid, is suitable for forming the solid dosage of solution or suspensoid before the injection in liquid, perhaps emulsion.Suitable vehicle is for example water, salt solution, glucose, glycerine or ethanol.In addition, if desired, the pharmaceutical composition of institute's administration also can comprise a spot of non-toxic auxiliary substances, and for example wetting agent or emulsifying agent, pH buffer reagent, stablizer, solubilizing agent and other these reagent are as sodium acetate, Arlacel-20, triethanolamine oleate and cyclodextrin.The present invention also comprises implantation slow release or sustained release system, to keep constant dosage level (for example referring to the 3rd, 710, No. 795 United States Patent (USP)s).Be included on the big extremely degree of per-cent of the active compound in the composition of these parenteral administrations and depend on character and the activity of compound and patient's the needs that it is concrete.
The parenteral administration preparation comprises vein, subcutaneous and intramuscular administration.The preparation of parenteral administration comprises the sterile solution that is used to inject, treat aseptic solubility dry-matter before use with solvent, as lyophilized powder, it comprises subcutaneous tablet, the aseptic suspensoid that is used to inject is treated and aseptic dry non-solubility material of carrier blended and no bacterial emulsion before use.Solution can be aqueous or water-free.
If intravenously administrable, suitable carriers comprise physiological saline or phosphate buffered saline (PBS) (PBS) and comprise tackify or the solution of the reagent of solubilising that mentioned reagent for example is glucose, polyoxyethylene glycol and polypropylene glycol and their mixture.
In the preparation of parenteral administration on the used pharmacology acceptable carrier comprise that aqueous carrier, non-aqueous carrier, antiseptic-germicide, isotonic agent, buffer reagent, oxidation inhibitor, local anesthetic, suspension and dispersion agent, emulsifying agent, sequestrant and other medicines are learned and go up acceptable material.
The example of aqueous carrier comprise sodium chloride injection, Ringers injection liquid, etc. ooze glucose injection, sterilized water injection liquid, glucose and lactic acid Ringers injection liquid.Non-aqueous parenteral administration carrier comprises fixed oil, Oleum Gossypii semen, Semen Maydis oil, sesame oil and the peanut oil of plant origin.The antiseptic-germicide that adds antibacterial or antifungal concentration in must the parenteral administration preparation in being packaged in multiple-dose container, described antiseptic-germicide comprise that phenol or cresols, mercurial, benzylalcohol, butylene-chlorohydrin, methyl p-hydroxybenzoate and propyl ester, thiomersal(ate), benzyl prick oronain and benzethonium chloride.Isotonic agent comprises sodium-chlor and glucose.Buffer reagent comprises phosphoric acid salt and Citrate trianion.Oxidation inhibitor comprises sodium pyrosulfate.Local anesthetic comprises vovocan.Suspension and dispersion agent comprise Xylo-Mucine, Vltra tears and polyvinylpyrrolidone.Emulsifying agent comprises Polysorbate80 (Tween 80).Metal ion chelation agent comprises EDTA.Pharmaceutical carrier also comprise ethanol, polyoxyethylene glycol and propylene glycol be used for can be miscible with water supporting agent, and sodium hydroxide, hydrochloric acid, citric acid or lactic acid are used for pH regulator.
The concentration of pharmaceutical active compounds can be regulated, so that injection can provide the compound of significant quantity, produces desirable effect of drugs.As is known to persons skilled in the art, accurate dose depends on age, body weight and the patient's condition of patient or animal.
The parenteral administration preparation of dosage unit can be packaged in the syringe of ampoule, phial or band syringe needle.As is known to persons skilled in the art, the preparation of the parenteral administration that is useful on must be aseptic.
For example, to comprise the aseptic aqueous solution of active compound be a kind of effective administering mode for vein or endoarterial infusion.Other embodiment is sterilized water or oil solution or suspension, comprising the necessary active injection mass of effect of drugs that produces hope.
Injection is used for fixed point or whole body administration.Generally, allocate the treatment effective dose into, its comprise at least about 0.1%w/w-90%w/w or more, preferably surpass the active compound of 1%w/w.Activeconstituents can disposable administration, also can be divided into the administration at certain intervals of a plurality of low doses.The exact dosage desired and the time that it should be understood that treatment change with treated tissue, and can use known testing scheme or by in body or vitro test data extrapolations determine empirically.Should also be noted that concentration and dose value also can change with the individual age of treatment.Further be understood that, for any patient, concrete dosage regimen should according to individual need and administration people or monitor drug-delivery preparation the people professional judgement and adjust in time, and said concentration only is exemplary, is not intended to limit the invention the scope or the actually operating of composition.
Compound can suspend into micronize or other suitable form, perhaps carries out derivatize to form more stable active result or to produce prodrug.The form of gained mixture depends on many factors, comprises administering mode and the compound solubleness in selected carrier or supporting agent.Effective concentration should be enough to alleviate the symptom of illness, and can determine empirically.
In many cases, compare with neutral compound, the solution of sodium salt comprises that sodium salt and sodium hydrogen phosphate have.In moisture medium, to compare with neutral compound, these salt also have higher solubleness.Find that in some aqueous compositions sodium salt is the same with sodium hydrogen phosphate salt stable.3, lyophilized powder
Making us interested especially is lyophilized powder, and this powder can restore with solution, emulsion or other mixture administration.They also can restore and be mixed with solid or gel preparation.
In specific embodiments, provide with respect to neutral sulphonamide preparation to have the more preparation of sulfonamide compounds salt, sodium hydrogen phosphate or sodium salt, the particularly sodium salt of high stability.Particularly, provide preparation as the sulphonamide sodium salt of aseptic freeze-dried powder.Find that these powder have higher stability with respect to neutral sulphonamide preparation.
Aseptic freeze-dried powder is prepared as follows: sodium salt is dissolved in the buffer solution of sodium phosphate that comprises glucose or other appropriate excipients, and this solution of sterile filtration, freeze-drying under standard conditions well known by persons skilled in the art then produces desirable preparation.In brief, lyophilized powder is prepared as follows: with dextrose, sorbyl alcohol, fructose, maize treacle, Xylitol, glycerine, glucose, sucrose or other suitable agent dissolves in suitable buffer, the amount of above-mentioned substance is about 1-20%, preferably be about 5-15%, described damping fluid is for example Citrate trianion, sodium phosphate or potassium or other damping fluids well known by persons skilled in the art, and this damping fluid is about pH neutral usually.Preferably be higher than room temperature, more preferably under about 30-35 ℃, selected sulfonamide, particular certain cancers be added to (about 1g salt/10-100g damping fluid is generally about 1g/30g) in the said mixture then, and stirring until dissolving.Add more damping fluid, dilute the mixture (make the about 10-50% of density loss of gained salt, be about 15-25% usually) of gained thus.The sterile filtration of gained mixture, perhaps aseptically process to be removing degranulation, and guarantees asepticly, and five equilibrium is put into the phial freeze-drying then.Each phial comprises the sulphonamide of single dosage (100-500mg, preferred 250mg) or many doses.Lyophilized powder can store under suitable condition, according to appointment 4 ℃-room temperature.The details of illustrative steps is seen embodiment.
This lyophilized powder restores the preparation that then can be provided for parenteral administration sulphonamide sodium salt with injection water.For recovery, add about 1-50mg, preferably 5-35mg, 9-30mg more preferably from about in every ml sterilized water or other suitable carriers.Accurate amount depends on the illness and the selected compound of being treated.This amount can be determined empirically.
In one embodiment, preparation comprises lyophilized solid, and it comprises one or more salt of the sulfonamide compounds of one or more formulas I, preferably phosphoric acid hydrogen sodium or sodium salt, and more preferably sodium salt, it also comprises one or more following materials:
Buffer reagent is as sodium phosphate or potassium, Citrate trianion;
Solubilizing agent is as LABRASOL, DMSO, two (trimethyl silyl) ethanamide, ethanol, propylene glycol (PG) or polyvinylpyrrolidone (PVP); And
Sugar is as sorbyl alcohol or glucose.
In a more preferred embodiment, preparation comprises one or more salt of the sulfonamide compounds of one or more formulas I, preferably phosphoric acid hydrogen sodium or sodium salt, more preferably sodium salt; Buffer reagent is as sodium phosphate or potassium or Citrate trianion; And sugar, as sorbyl alcohol or glucose.
In the most preferred embodiment, preparation comprises one or more sodium salts of the sulfonamide compounds of one or more formulas I; Sodium phosphate buffer agent; And glucose.4, topical
Topical can prepare as above fixed point and whole body administration.The gained mixture can be solution, suspension, emulsion etc., and can be mixed with ointment, gelifying agent, ointment, latex, solution, elixir, lotion, suspensoid, tincture, paste, foaming agent, aerosol, filling agent, sprays, suppository, bandage, medicine subsides or any other formulations that are suitable for topical.
The sodium salt of The compounds of this invention and other derivatives may be molded to the aerosol of topical, as inhalation (referring to for example: the 4th, 044,126,4,414,209 and 4,364, No. 923 United States Patent (USP)s, they have described the aerosol of the steroid drugs that is used for drug treatment inflammatory diseases, particularly asthma).These preparations to respiratory tract administration can be aerosol or the solution that is used for atomizer, are the fines that is used to suck perhaps, and active substance can use separately or be used in combination with inert support such as lactose.In the case, particle grain size is less than 50 microns, preferably less than 10 microns in the preparation.
The sodium salt of compound can be mixed with and be used for fixed point or topical, and for example the part is used for skin and mucous membrane, in eye, is gelifying agent, ointment and lotion, and can be used in eye or the brain pond or in the backbone.Topical also comprises transdermal administration, and to eye or mucosa delivery, or be used for sucking treatment.But the also independent active compounds solution of intranasal administration or learn with other drug and to go up acceptable excipient composition administration.
These solution, particularly those are used for the solution of ophthalmology, and available suitable salt is mixed with the isotonic solution of 0.01-10%, and the pH value is about 5-7.5, finished product
At last, the derivative of this compound, particularly salt, acid, ester and prodrug, particular certain cancers, can be packaged into finished product, wherein contain wrapping material, being contained in this paper in the wrapping material provides effective antagonism endothelium peptide effect, improves the symptom of the pathology that the endothelium peptide regulated or suppresses the endothelium peptide and ET receptors bind, IC 50Be lower than salt, acid, ester and prodrug, the particular certain cancers of the compound of 10 μ M, and illustrate that this compound or its salt can be used for pathology that antagonism endothelium peptide effect, treatment endothelium peptide regulated or the label that suppresses endothelium peptide and ET receptors bind.6, the preparation that is used for other administration route
According to the illness of being treated, other administration route is as topical, transdermal patch, rectal administration, also within the scope of the invention.
For example, the pharmaceutical dosage form of rectal administration is rectal suppository, capsule and the tablet with general action.Be meant the solid objects that is inserted in the rectum at this used rectal suppository, this object can melt under body temperature or be softening, discharges one or more pharmacology or therapeutic activity composition.In the rectal suppository on the used pharmacology acceptable material be matrix or carrier and the reagent that improves fusing point.The example of matrix comprise theobroma oil (theobroma oil), glycerine-gelatin, carbon ester polyoxyethylene glycol, (polyoxyethylene glycol) and glycerine single, two and the mixture of tri-fatty acid ester.The suppository that improves the suppository fusing point comprises spermaceti and beeswax.Rectal suppository can be by compression or moulding method preparation.The common weight of rectal suppository is about 2-3g.
The tablet of rectal administration and capsule can use on the pharmacology identical with the preparation of oral administration acceptable material and method to make.
The following example only illustrates the present invention, does not limit the scope of the invention.
Embodiment 1N-(2-ethanoyl-4,6-3,5-dimethylphenyl)-3-{[(3,4-dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-2-thiophenecarboxamides step 1: preparation compound 1
The 5-amino-3 that in being furnished with the 250ml round-bottomed flask of magnetic stirring bar, adds 20.0g, the dimethyl aminopyridine of the pyridine of 4-dimethyl isoxazole, 50ml and 2.0g (catalytic amount).This mixture of cooling, 2-carboxymethyl-3-thiophene SULPHURYL CHLORIDE of portion-wise addition 21.5g simultaneously in ice bath.Seal this flask, remove ice bath, at room temperature reaction stirred is spent the night then.Remove the pyridine of the overwhelming majority by rotary evaporation, residue distributes between ethyl acetate and 2 N hydrochloric acid.Separate each layer, and extract the waterbearing stratum with ethyl acetate (2 *).The extraction liquid that merges is with dilute hydrochloric acid (2 *), salt solution (2 *) washing, and is dry on sal epsom then.Filtration and rotary evaporation concentrate, and obtain 23.2g buttery compound 1.Step 2: preparation compound 2
Be furnished with compound 1, the methylene dichloride of 500ml and the diisopropylamine of 28.4g that adds 23.1g in the round-bottomed flask of magnetic stirring bar and dropping funnel at 1L.In ice bath, cool off reactant, drip the brooethyl methyl ether of 6.0ml then.Remove ice bath, at room temperature reaction stirred is spent the night then.At this moment, add the water of 200ml, and reaction stirred 30 minutes.Separate each layer, and with dichloromethane extraction waterbearing stratum (2 *).The organic layer that merges is with 0.5N hydrochloric acid, water, saturated sodium bicarbonate aqueous solution, salt water washing, and is dry on sal epsom then.Filter and rotary evaporation, obtain an oily matter, it further carries out pure system with the 25-30% ethyl acetate/hexane as eluent by silica gel chromatography, obtains 21.5g buttery compound 2.Step 2B: preparation compound 3
Figure A0081806101082
Is furnished with compound 2, the tetrahydrofuran (THF) of 120ml and the 1N sodium hydroxide of 120ml that adds 21.4g in the round-bottomed flask of magnetic stirring bar at 500ml.Quick reaction stirred is until react completely (about 3-4 hour).Remove most tetrahydrofuran (THF)s by rotary evaporation, then residue is mixed with the water of 50ml.This mixture carries out acidifying with the 1N hydrochloric acid of 130ml, uses the ethyl acetate extraction (* 2) of 200ml then.Dried over mgso is used in the extraction liquid water (50ml) that merges, salt solution (50ml) washing at last.After filtration and rotary evaporation concentrate, obtain the compound 3 of 20.1g yellow oily, it solidifies when placing.Step 2C: preparation compound 4
Figure A0081806101091
Are furnished with the compound 3 that adds 19.7g in the round-bottomed flask of magnetic stirring bar and dropping funnel, methylene dichloride and 5 pyridines of 200ml at 1L.Drip the solution of 128ml oxalyl chloride in the 100ml methylene dichloride.Change dropping funnel into reflux exchanger, and reactant is heated to backflow 3 hours, concentrate by rotary evaporation afterwards, obtain the compound 4 of 20.9g brown solid shape.This material is directly used in the step 3 without pure system.Step 3: preparation compound 6
Figure A0081806101101
Be furnished with the 2-ethanoyl-4 that adds 18.5g in the round-bottomed flask of magnetic stirring bar and dropping funnel, the methylene dichloride of 6-xylidine (5) and 150ml at 1L.To the solution of compound 4 in the 350ml methylene dichloride that wherein drips 20.7g.At room temperature reaction stirred is 3 hours, then evaporation concentration.In residue, add the ether of 20ml, and filter this mixture.Filter cake washs with the ether of 3 * 100ml.The filtrate that merges is used water, saturated sodium bicarbonate aqueous solution and the salt water washing of 100ml respectively then with the 1N salt acid elution of 3 * 100ml.The solution dried over mgso is filtered, and rotary evaporation concentrates then, produces semi-crystalline materials.This material grinds with the ether of 200ml, obtains the compound 6 of 23.7g, and it is a white solid.Step 4A: preparation compound 7
Figure A0081806101111
Be furnished with compound 6, the methyl alcohol of 180ml and the concentrated hydrochloric acid of 90ml that adds 23.7g in the round-bottomed flask of magnetic stirring bar and reflux exchanger at 500ml.Mixture heating up was refluxed 4 hours.Stop heating, stir the mixture then, and cool off with ice bath.After about 30 minutes, filtering mixt, filter cake water and methanol mixture are washed, and obtain the compound 7 of 18.3g.This material ethyl acetate/hexane recrystallization obtains the material of 16.8g white solid: mp 158-160 ℃.Step 4B: preparation compound 7 sodium salts
Figure A0081806101121
The compound 7 of 16.8g is dissolved in the tetrahydrofuran (THF) of the ethyl acetate of 800ml and 200ml, and to the saturated sodium bicarbonate aqueous solution that wherein adds 100ml.Separate each layer, and wash organic layer with extra 2 * 100ml saturated sodium bicarbonate aqueous solution.The sodium bicarbonate washings that merges is used ethyl acetate extraction again, and the organic solution of merging is dry on sal epsom, filters, and rotary evaporation concentrates then, obtains a foam-like material.This substance dissolves is filtered the solution and the freeze-drying of gained then in the water of 300ml, obtain compound 7 sodium salts of 15.5g, and it is a white solid.
Embodiment 2N-(2-cyano group-3,4,6-trimethylphenyl)-3-{[(3,4-dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides
Figure A0081806101131
Method according to embodiment 1 prepares N-(2-cyano group-3,4,6-trimethylphenyl)-3-{[(3; 4-dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides, but in step 3, use 2-cyano group-3,4; 6-trimethylaniline (8) is replaced 2-ethanoyl-4,6-xylidine.
Embodiment 3 preparation compound 16:3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-N-(3; 4,6-trimethylammonium-2-propionyl phenyl)-2-thiophenecarboxamides step 1: amino preparation compound 10:3-{[(4-chloro-3-methyl-5-isoxazolyl)] alkylsulfonyl }-the 2-thiophenic acid
Figure A0081806101141
The 3-{[(4-chloro-3-methyl-5-isoxazolyl that in the 500ml round-bottomed flask, adds 46.5g) amino] alkylsulfonyl }-the 2-thiophenecarboxylate, add the 1N sodium hydroxide solution of 250ml then.Stir the mixture, until there not being any initiator.With 2N hydrochloric acid acidizing reaction solution, use ethyl acetate (3 * 100ml) extractions then.The extract drying (sal epsom) that merges is filtered and rotary evaporation concentrates, and obtains compound 10 solids of 42.5g.Step 2A: amino preparation 3-{[(4-chloro-3-methyl-5-isoxazolyl)] alkylsulfonyl }-N-methoxymethyl-2-thiophenic acid methoxymethyl ester
Figure A0081806101142
Be furnished with compound 10, the methylene dichloride of 500ml and the diisopropyl ethyl amine of 40.1g that adds 42.5g in the round-bottomed flask of magnetic stirring bar and dropping funnel at 2L.Use the ice bath reaction mixture, drip the brooethyl methyl ether of 21.5ml then.Car falls ice bath, and at room temperature reaction stirred is spent the night then.Add the water of 200ml, and stirred reaction mixture 30 minutes.Separate each layer, and with 100ml dichloromethane extraction waterbearing stratum.Merge organic layer and also use 0.5N hydrochloric acid, water, saturated sodium bicarbonate aqueous solution, the salt water washing of 50ml respectively, use dried over mgso at last.Mixture filters, and rotary evaporation filtrate, obtains an oily matter, and it further carries out pure system with the 25-30% ethyl acetate/hexane as eluent by silica gel chromatography, obtains 38.1g buttery compound 11.
Step 2B: preparation compound 12
Is furnished with compound 11, the tetrahydrofuran (THF) of 250ml and the 1N sodium hydroxide of 250ml that adds 38g in the round-bottomed flask of magnetic stirring bar at 1L.Quick reaction stirred is until scope complete (about 4 hours).Remove the tetrahydrofuran (THF) of the overwhelming majority by rotary evaporation, residue is mixed with the water of 50ml.This solution carries out acidifying by the 1N hydrochloric acid that adds 260ml.With twice in this mixture of ethyl acetate extraction of 200ml.The extraction liquid that merges is used water and the salt water washing of 50ml respectively, uses dried over mgso then.Filtration and rotary evaporation concentrate, and obtain the compound 12 of 30.8g yellow oily, and it solidifies when placing.Step 2C: preparation compound 13
Are furnished with the compound 12 that adds 30g in the round-bottomed flask of magnetic stirring bar and dropping funnel, methylene dichloride and 5 pyridines of 20ml at 1L.Add the solution of thionyl chloride in the 200ml methylene dichloride of 29.2g.Change dropping funnel into reflux exchanger, then with reactant reflux 4 hours.Come the concentration response thing by rotary evaporation, obtain the compound 13 of 31.4g, it is a brown solid.This material promptly is directly used in the step 3 without further pure system.Step 3: preparation compound 15
Figure A0081806101162
Be furnished with the compound (14) that adds 19.8g in the round-bottomed flask of magnetic stirring bar and dropping funnel and the methylene dichloride of 150ml at 1L.To the solution of compound 13 in the 350ml methylene dichloride that wherein drips 20.0g.Reactant at room temperature stirred 3 hours, and rotary evaporation concentrates then.In residue, add the ether of 200ml, filter this mixture then.Filter cake washs with the ether of 100ml, the hot ethyl acetate of 2 * 200ml.The washings that merges is with the 1N hydrochloric acid of 3 * 100ml, the water that is respectively 100ml, saturated sodium bicarbonate aqueous solution and salt water washing.The solution dried over mgso is filtered, and rotary evaporation concentrates then, obtains the semi-crystalline material.This material grinds with the ether of 100ml, obtains the compound 15 of 20.1g, and it is a white solid.Step 4: preparation compound 16
According to the method for embodiment 1, the compound 15 of step 4A is converted into compound 16, it is a solid, mp 166-170 ℃.
Embodiment 4 preparation compound 18:3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-N-[2-(1-hydroxyethyl)-4, the 6-3,5-dimethylphenyl]-the 2-thiophenecarboxamides
Figure A0081806101181
In the solution of compound 17 (sodium salt) Yu Shuizhong of 100mg, add the sodium borohydride of 100mg.After 3 hours, add other 100mg sodium borohydride, at room temperature stirred solution spends the night then.Reactant mixes with excessive saturated nacl aqueous solution, with ethyl acetate (3 * 50ml) extractions.Extraction liquid washs with saturated sodium bicarbonate aqueous solution, and evaporation obtains compound 18 (sodium salt) then, and it is a solid, mp 147-154 ℃.
Embodiment 5 preparation compound 20:3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-the N-{2-[(dimethylamino) carbonyl]-4, the 6-3,5-dimethylphenyl }-the 2-thiophenecarboxamides
Figure A0081806101191
Method according to embodiment 3 prepares compound 20, but uses the 2-[(dimethylamino in step 3) carbonyl]-4,6-xylidine (19) is replaced compound 12.The compound 20 of gained is a white solid.
Embodiment 6 preparation compound 22:3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-N-{2,4-dimethyl-6-[(methoxyl group) ethanimidoyl] phenyl }-the 2-thiophenecarboxamides
Compound 17 and methoxyl group amine (21) are reacted in ethanolic soln, obtain the compound 22 of white solid, mp 140-145 ℃.
Embodiment 7 preparation compound 24:3-{[(3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-the 2-thienyl) carbonyl] amino }-2,4,6-trimethylphenyl-N, N-dimethylamino sulphonate
At the 3-{[(4-of 700mg chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-{3-hydroxyl-2,4, the 6-trimethylphenyl }-add the potassium tert.-butoxide of 247mg in the ice-cold solution of 2-thiophenecarboxamides (23) in the 15ml dimethyl formamide.After short period of time, add the dimethylamino SULPHURYL CHLORIDE of 317mg.Judge that dilute with water is used the 1N hcl acidifying when reacting completely.(3 * 30ml) extract this mixture, and the extraction liquid drying (sal epsom) of merging, filtration are evaporated then, obtain the compound 24 of white solid with ethyl acetate; Mp 169-174 ℃.
Embodiment 8 preparation compound 26:3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-N-{3-[(cyclopropyl methyl) the oxygen base]-2,4, the 6-trimethylphenyl }-the 2-thiophenecarboxamides
At the 3-{[(4-of 700mg chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-{3-hydroxyl-2,4, the 6-trimethylphenyl }-add the potassium tert.-butoxide of 247mg in the ice-cold solution of 2-thiophenecarboxamides (23) in the 15ml dimethyl formamide.After short period of time, add the cyclopropyl monobromomethane (25) of 135mg.Judge that dilute with water is used the 1N hcl acidifying when reacting completely.(3 * 30ml) extract this mixture, and the extraction liquid drying (sal epsom) of merging, filtration are evaporated then, obtain the compound 26 of white solid with ethyl acetate; Mp 155-158 ℃.
Embodiment 9 preparation compound 28:3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-N-(2,4,6-trimethylammonium-5-pyrimidyl)-2-thiophenecarboxamides
Method according to embodiment 3 prepares compound 28, but uses 5-amino-2,4 in step 3, and 6-trimethylammonium pyrimidine (27) is replaced compound 12.The compound 28 of gained is a white solid; Mp 170-175 ℃.
Embodiment 10 preparation compound 30:N-(2-ethanoyl-3,4,6-trimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-the 2-thiophenecarboxamides
Figure A0081806101241
Method according to embodiment 3 prepares compound 30, but uses 2-ethanoyl-3,4 in step 3, and 6-trimethylaniline (29) is replaced compound 12.The compound 30 of gained is a white solid; Mp 223-225 ℃.
Embodiment 11 preparation compound 32:3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-N-(2-cyano group-3,4,6-trimethylphenyl)-2-thiophenecarboxamides
Method according to embodiment 3 prepares compound 32, but uses 2-cyano group-3,4 in step 3, and 6-trimethylaniline (31) is replaced compound 12.The compound 32 of gained is a white solid; Mp 218-220 ℃.
Embodiment 12 preparation compound 34:N-(2-chloro-4,6-3,5-dimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-the 2-thiophenecarboxamides
Method according to embodiment 3 prepares compound 34, but uses 2-chloro-4 in step 3, and 6-xylidine (33) is replaced compound 12.The compound 34 of gained is a white solid; Mp 174-176 ℃.
Embodiment 13 preparation compound 36:3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-N-(4,6-diacetyl-3-hydroxyl-2-propyl group phenyl)-2-thiophenecarboxamides
Method according to embodiment 3 prepares compound 36, but in step 3 with 4,6-diacetyl-3-hydroxyl-2-propyl group aniline (35) is replaced compound 12.The compound 36 of gained is a white solid; Mp 163-167 ℃.
Embodiment 14 preparation compound 38:3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-N-(2,4-dimethyl-6-[2-(methyl sulphonyl) ethanoyl] phenyl)-the 2-thiophenecarboxamides
Figure A0081806101281
Method according to embodiment 3 prepares intermediate compound 53, but in step 3 with 2,4-dimethyl-6-(2-chloracetyl) aniline (37) is replaced compound 12.
At room temperature stir the compound 53 of 400mg and the solution of methanesulfonic sodium in the 10ml dimethyl formamide of 1.2g.When judgement reacted completely, the reactant dilute with water was used the 2N hcl acidifying, and (3 * 30ml) extract with ethyl acetate.Combining extraction liquid, drying, rotary evaporation concentrates then, obtains compound 38, and it is a white solid; Mp172-175 ℃.
Embodiment 15 preparation compound 40:3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-N-(2,4-dimethyl-6-{[methyl (2, the 2-dimethyl propyl) amino] carbonyl } phenyl)-the 2-thiophenecarboxamides
Method according to embodiment 3 prepares compound 40, but uses the 2-{[methyl in step 3-(2, the 2-dimethyl propyl) amino] carbonyl }-4,6-xylidine (39) is replaced compound 12.The compound 40 of gained is a white solid; Mp 174-176 ℃.
Embodiment 16 preparation compound 42:3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-N-[2,4-dimethyl-6-(methyl sulphonyl) phenyl]-the 2-thiophenecarboxamides
Figure A0081806101301
Method according to embodiment 3 prepares compound 42, but in step 3 with 2,4-dimethyl-6-(methyl sulphonyl) aniline (41) is replaced compound 12.The compound 40 of gained is a white solid; Mp 208-210 ℃.
Embodiment 17 preparation compound 44:3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-N-[2,4-dimethyl-6-(1,3-oxazoles-2-yl) phenyl]-the 2-thiophenecarboxamides
Figure A0081806101311
Method according to embodiment 3 prepares compound 44, but in step 3 with 2,4-dimethyl-6-(1,3-oxazoles-2-yl) aniline (43) is replaced compound 12.The compound 44 of gained is a white solid; Mp 176-178 ℃.
Embodiment 18 preparation compound 46:3-{[(4-chloro-5-isoxazolyls) amino] alkylsulfonyl }-N-[2-(2-sulfonyl propyl base)-4, the 6-3,5-dimethylphenyl]-the 2-thiophenecarboxamides
Figure A0081806101321
Method according to embodiment 3 prepares compound 46, but uses 2-(2-sulfonyl propyl base)-4 in step 3, and 6-xylidine (45) is replaced compound 12.The compound 46 of gained is a white solid; Mp 190-192 ℃.
Embodiment 19 preparation compound 48:3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-N-[2,4-dimethyl-6-(sulfonyl propyl base) phenyl]-the 2-thiophenecarboxamides
Figure A0081806101331
Method according to embodiment 3 prepares compound 48, but in step 3 with 2,4-dimethyl-6-(sulfonyl propyl base) aniline (47) is replaced compound 12.The compound 40 of gained is a white solid; Mp 152-155 ℃.
Embodiment 20 preparation compound 50:3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-N-[2-ethyl-4, the 6-3,5-dimethylphenyl]-the 2-thiophenecarboxamides
Method according to embodiment 3 prepares compound 50, but uses 2-ethyl-4 in step 3, and 6-xylidine (49) is replaced compound 12.The compound 50 of gained is a white solid; Mp 152-154 ℃.
Embodiment 21 preparation compound 52:3-{[(4-chloro-3-methyl-5-isoxazolyls) amino] alkylsulfonyl }-N-[2,6-dimethyl-4-(1,3-oxazoles-2-yl) phenyl]-the 2-thiophenecarboxamides
Figure A0081806101351
Method according to embodiment 3 prepares compound 52, but in step 3 with 2,6-dimethyl-4-(1,3-oxazoles-2-yl) aniline (51) is replaced compound 12.The compound 52 of gained is a white solid; Mp 205-207 ℃.
Embodiment 22The sulphonamide sodium salt preparation of the preparation A of sulphonamide sodium salt, intravenously administrable
In 4 liters of graduated cylinders that scale arranged, add 3200ml sterile water for injection (USP), in this sterilized water, add seven water Sodium phosphate dibasic (USP, 21.44g), stirred this mixture 5 minutes, and perhaps dissolved fully, add SODIUM PHOSPHATE, MONOBASIC (USP until solid, 11.04g), stir the mixture and dissolve fully,, make damping fluid thus solution dilution to 4.0 liter also stirring until solid.The phosphate buffered saline buffer that 3000g is made is added in 8 liters of beakers.(USP 200.0g), and is heated to 30-35 ℃ with mixture in water-bath, stir simultaneously until forming solution to add glucose.Add the sulphonamide sodium salt (100.0g) that is mixed with vehicle.Stirred this mixture at least 10 minutes or until forming solution.Treat from water-bath, to take out solution after the sodium salt dissolving.With phosphate buffered saline buffer with this solution dilution to 4000g, and stirred 5 minutes.Use DuraporeMillipak 200 these solution of strainer sterile filtration in aseptic 0.22 micron prefabricated aperture.Filtered solution is packed in the aseptic phial, and freeze-drying under standard conditions.Seal this phial.Lyophilized products is restored with the water for injection of 9.4ml or 19.4ml then, and the ultimate density of formation is respectively 25mg/ml or 12.5mg/ml.B, be used for the sulphonamide sodium salt preparation of oral administration
Use method known to those skilled in the art prepare these preparations (for example referring to Ansel, Introduction to Pharmaceutical Dosage Forms(the 4th edition) 1985 (Lea﹠amp; Febiger)).Generally, make each composition granulating with wet method or dry method, compression prepares tablet thus then.In addition, the composition of combination can form tablet by direct compression.When the preparation capsule, sulphonamide sodium salt, vehicle (thinner), tackiness agent, disintegrating agent and lubricant are directly inserted in the capsule shell.The appropriate amount of activeconstituents and inert fraction can be determined by method known to those skilled in the art empirically in these preparations.Generally, the amount of activeconstituents (being the sulphonamide sodium salt) should be enough to produce the activeconstituents of treatment effective dose.The treatment effective dose can be by test compounds in known body and in the vitro system (for example referring to the 5th, 114, No. 918 United States Patent (USP)s of people such as Ishikawa; EP A10436189, BANYUPHARMACEUTICALCO., LTD. (on October 7th, 1991); People such as Borges (1989) Eur.J.Pharm.165: 223-230; People such as Filep (1991) Biochem.Biophys.Res.Commun.177: the dosage that is used for the people of 171-176) and then thus extrapolating is determined empirically.
Embodiment 23Differential method with compound of endothelin antagonists and/or agonist activity
Compound with endothelin antagonists potentiality by its with 125The ET-1 of I mark is competing in conjunction with people ET on the cytolemma of separation AAcceptor or ET BThe ability of acceptor is differentiated.Test compound also can be assessed by the influence of the contraction that the endothelium peptide brought out by measuring its mouse thoracic aorta link to separation as the validity of the antagonist of the biological tissue of endothelium peptide reaction or agonist.Compound is as ET BThe antagonist of acceptor or the ability of agonist can suppress the ability that endothelium peptide-1 brings out the bovine aortic endothelial cells delivery of prostacyclin of being cultivated by test compound and decide.A, inhibition endothelium peptide keying action-combination test #1: suppress and ET AThe effect of receptors bind
TE671 cell (ATCC No.HTB 139) is expressed ET AAcceptor.These cells grow to fusion in the T-175 flask till.In most multiple flasks, scrape cell and pool together, under 190 * g centrifugal 10 minutes.Use the Tenbroeck homogenizer, with cell suspension in the phosphate buffered saline that contains 10mMEDTA (PBS).Suspension under 4 ℃, 57800 * g centrifugal 15 minutes, throw out resuspending is in 5ml buffer A (5mM HEPES damping fluid, pH7.4 comprise aprotinin (100KIU/ml)), and is freezing then and thaw once.(5mM HEPES damping fluid, pH7.4 contains 10mM MnCl to add the 5ml buffer B 2With 0.001% deoxyribonuclease I), counter-rotating suspension mixes, and cultivates 30 minutes down in 37 ℃ then.As mentioned above, mixture is centrifugal under 57800 * g, after throw out washs 2 times with buffer A, resuspending is in damping fluid C (30mM HEPES damping fluid, pH7.4 contain aprotinin (100KIU/ml)), the protein final concentration is 2mg/ml, be kept under-70 ℃, when using till.
(30mM HEPES damping fluid, pH7.4 contain 150mM NaCl, 5mM MgCl with the keying action damping fluid 2, 0.5% bacitracin) concentration of dilution film suspension to 8 μ g/50 μ l.Interpolation 125I-endothelium peptide-1 (3000cpm, 50ml) to it (A) endothelium peptide-1 (being used for non-specificity keying action) of 50 μ l, final concentration is 80nM; (B) keying action damping fluid (being used for the total binding effect); Or (C) in the test compound (final concentration 1nM to 100 μ M).Get the film suspension (50 μ l) that comprises 8 μ g membrane proteins add to each (A), (B) or (C) in.Oscillation mixture was cultivated 16-18 hour down in 4 ℃, under 4 ℃ and 2500 * g centrifugal 25 minutes again.Perhaps, cultivate down in 24 ℃.When cultivating down for 24 ℃, IC 50Concentration ratio is high 2 to 10 times when cultivating down for 4 ℃.Therefore, provide IC between the compound as this paper relatively 50During concentration, must be noted that this point.
Decant comprises the supernatant liquor of the radioactivity of not combination, and taking precipitate is counted on Genesys microporous gamma counter.Calculate the degree (D) that suppresses keying action according to following formula: % D = 100 - ( C ) - ( A ) ( B ) - ( A ) × 100
Every test is carried out three times usually.B, inhibition endothelium peptide keying action-combination test # 2: suppress and ET BThe effect of receptors bind
With coding ET BThe DNA rotaring redyeing COS 7 cell of acceptor.But the expressing human ET that is produced BThe cell of acceptor grows to fusion in the T-150 flask.According to the method for preparing film.Use film preparation, be diluted to the concentration of 1 μ g/50 μ l, carry out the keying action analysis according to above-mentioned with the keying action damping fluid.
In brief, by the above-mentioned ET that encodes that accepted BThe DNA transfection of acceptor is also gone up expressing human ET in its surface BThe COS7 cell of acceptor grows to fusion in the T-175 flask.In the flask that majority heavily covers, scrape cell and pool together, centrifugal 10 minutes in 190 * g.Use the Tenbroeck homogenizer, make cell suspension in the phosphate buffered physiology salt (PBS) that contains 10mM EDTA.Suspension under 4 ℃, 57800 * g centrifugal 15 minutes, throw out floats on 5ml buffer A (5mMHEPES damping fluid, pH7.4 contain and press down proteolytic enzyme (100KIU/ml)) again, and is freezing then and thaw once.(5mM HEPES damping fluid, pH7.4 contains 10mM MnCl to add the 5ml buffer B 2With 0.001% deoxyribonuclease I), counter-rotating suspension mixes, and cultivates 30 minutes down in 37 ℃ then.Mixture is according to above-mentioned, and is centrifugal under 57800 * g, and after throw out washed 2 times with buffer A, resuspending was in damping fluid C (30mM HEPES damping fluid, pH7.4 contain aprotinin (100KIU/ml)), and the protein final concentration is 2mg/ml.
According to above-mentioned, use the film preparation that is diluted to 1 μ g/50 μ l keying action damping fluid, carry out the keying action analytical method.C, antagonism endothelium peptide bring out the mouse thoracic aortic ring of separation and the active test of contracting
Test compound as the efficiency analysis method of the antagonist of the biological tissue of endothelium peptide reaction or agonist be by the contraction of measuring its mouse thoracic aortic ring of the endothelium peptide being brought out separation influence (for example see: people such as Borges (1981), Eur.J.Pharmacol.165:223-230) or measure that the ability that makes tissue contracts when it adds separately estimates.
Test compound is made 100 μ M preserve liquid.If must dissolving, compound is dissolved among the DMSO, dilute with 150mM NaCl.Because DMSO can make aortic annulus loosen, therefore test contains the control group solution of different concns DMSO.
Have of one's own and downcut the thoracic aorta part on the mouse aorta, carefully peel endothelium, be cut into 3 millimeters links.Link at 2g preload amount low suspension in the 10ml organ bath.Fill with 95%O in the organ bath 2And 5%CO 2The Krebs ' that gaseous mixture is saturated-Henseleit solution (118mM NaCl, 4.7mM KCl, 1.2mM MgSO 4, 1.2mM KH 2PO 4, 25mM NaHCO 3, 2.5mMCaCl 2, 10mM D-glucose).
Bring out as the endothelium peptide between the activity of antagonist of thoracic aortic ring contraction and the activity dependency is arranged as the inhibitor of endothelium peptide and the effect of endothelium peptide receptors bind.PA 2Be IC 50The linear function of logarithmic value.D, to ET BAcceptor has the differential method of the compound of agonist and/or antagonistic activity 1, stimulate prostacyclin to discharge
Because the bovine aortic endothelial cells delivery of prostacyclin of endothelium peptide-1 thorn regular menstruation during early pregnancy cultivation is therefore haply according to people such as Filep (1991) Biochem.Biophys.Res.Commun.177The described mensuration of 171-176 6-ketone group PGF 1 α, suppress the ability that endothelium peptide-1 brings out these endothelium polypeptide cell delivery of prostacyclin by compound, identify compound with agonist or antagonistic activity.The bovine aortic cell bovine aortic that collagen is handled of hanging oneself, be seeded in the culture dish, in 199 substratum of 15% foetal calf serum that replenishes heat inactivation and L-glutamine (2mM), penicillin, Streptomycin sulphate and fungizone, grow, and be cultured to few 4 times.Cell is inoculated in six orifice plates of same medium.After treating that cell reaches fusion, change substratum in analyzing preceding 8 hours.Cell again a) with the substratum single culture, b) with contain the culture medium culturing of endothelium peptide-1 (10nM), c) with the test compound single culture, and d) cultivate with test compound+endothelium peptide-1 (10nM).
Cultivate after 15 minutes, take out the substratum in each hole, by direct immunization assay 6-ketone group PGF 1 αConcentration is by the 6-ketone group PGF of the cell release of accepting endothelium peptide-1 processing 1 αAmount deducts the amount of accepting same treatment but not being subjected to the cell release of endothelium peptide-1 processing, calculates prostacyclin output by its difference.Can stimulate 6-ketone group PGF 1 αThe compound that discharges has agonist activity, and those suppress endothelium peptide-1,6-ketone group PGF 1 αThe compound that discharges then has antagonistic activity. 2, suppress the contraction that Sha Luofu toxin 6c is brought out
Sha Luofu toxin 6c is specificity ET BAntagonist makes that the stripping bar shrinks at the bottom of the stomach of rats.Adopt test compound to suppress the validity of stripping bar contraction at the bottom of the stomach of rats that this Sha Luofu toxin 6c brought out, as ET BThe measured value of antagonistic activity.Get 2 stripping bars at the bottom of the stomach of rats of separation, in organ bath, organ bath is filled and to be comprised 10 μ M rings (D-Asp-Pro-D-Val-Leu-D-Trp), 5 μ M indomethacins and with 95%O at 1g charge capacity low suspension 2/ 5%CO 2Kreb ' s-Henseleit solution (the BQ-123 that gaseous mixture is saturated; The 5th, 114, No. 918 United States Patent (USP)s referring to people such as Ishikawa).Under equivalent, measure tensile and change, and adopt the GrassPolygraph record that is connected in transmodulator.Add Sha Luofu toxin 6c to one of them stripping bar with the progression formula, get second stripping bar simultaneously and cultivated 15 minutes with test compound is pre-earlier, and then add the Sha Luofu toxin 6c of progression dosage.The check test compound is to the influence of concentration one response curve of Sha Luofu toxin 6c.E, with deoxycorticosterone acetate (DOCA) hypertension rat model in the activity of in vivo analyzing specific compound
Test several specific compounds disclosed herein in deoxycorticosterone acetate (DOCA) hypertension rat model.When carrying out these tests, according to people such as Ommsbee (1973), The J. Pharm.Sci.62: the method for 255-257, preparation contains the silicon rubber MDX4-4210 elastomerics implant of 47mg DOCA.In brief, DOCA is added in the silicon rubber implant, make it to continue to discharge.During the preparation implant, DOCA is added in the unpolymerized silicon rubber, add catalyzer, then mixture is moulded half round post.
Get Sprague Dawley mouse (7 to 8 week big), under Patients Under Ketamine Anesthesia, carry out unilateral nephrectomy, with the DOCA-implant on the abdomen back side, an animal left side.Make mouse recover for 3 weeks.Between decubation, can freely take normal mouse feed, and use the alternative drinking-water of 0.9%NaCl drinkable solutions instead.Mouse is developed in 3 weeks and hypertension.
All animals all are used for test between back 21 days to 30 days in operation.The mean arterial blood pressure of these animals is in the scope of 165-200 mmhg.
Experiment same day, in methohexital (brevital) anesthesia down, conduit inserted be used to measure blood pressure in the right femoral artery, and be used for the administration specific compound in the insertion right femoral vein.Animal is inserted in the fence, made it to recover at least 60 minutes, or till recording stably mean arterial blood pressure.At this moment, infuse with 60 minutes through intravenously, or the per os conduit gives specific compound or control group supporting agent.Continuous blood pressure measuring is 10 hours again.F, the influence that the mensuration specific compound reacts the vassopressin that ET-1 brought out through intravenous administration in the activity in vivo vivid analytical model of the rat that clear-headed autonomy is blocked
(methohexital 50mg/kg, IP) male Sprague Dawley mouse (250-450g) insert conduit and measure mean arterial pressure (MAP) in the femoral artery, insert femoral venous conduit and then supply through intravenous administration in anesthesia.Animal is inserted in the fence, makes it to recover consciousness.After 30 minutes, and administration autonomy blocker (coromegine methyl nitrate, 3mg/kg, IV, administration Propranololum (propranalol) subsequently, 2mg/kg, IV).After 1 hour, animals received bolus supporting agent injection (0.5ml) is after 30 minutes, through intravenously bolus administration ET-1 (control group, 1 μ g/kg).By after accepting these and recovering in handling,, give ET-1 after 30 minutes again through intravenously bolus medicine-feeding test compound (0.5ml).The vassopressin reaction that the result brings out ET-1 after with the medicine-feeding test compound with accept control group ET-1 and handle the vassopressin that is brought out and react the restraining effect per-cent that relatively obtains and represent.Sometimes just carrying out for the third time after 90 minutes at the medicine-feeding test compound, ET-1 handles.G, result 1, external
The previous embodiment compound is to ET AAnd ET BEach IC of acceptor 50All measure.Nearly all compound is to ET AAnd ET BThe IC of acceptor one or both of 50All be lower than 10 μ M.The IC of chemical compound lot 50Be lower than 10 μ M, the IC of other compounds 50Be lower than about 1 μ M, the IC of some compound 50Be lower than about 0.1 μ M.Chemical compound lot is to ET AThe IC of acceptor 50Far below (10 to 100 times or more) to ET BAcceptor is therefore to ET AAcceptor tool selectivity.Other compounds are then to ET BAcceptor tool selectivity. 2, in vivo
All in the hypertension rat model, tested several specific compounds,, and can effectively bring high blood pressure down as N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxyl-2,4,6-trimethylphenyl aminocarboxyl) thiophene-3-sulphonamide.
Embodiment 24
The experiment A of the toxicology character of assessment compound, cytochrome P 450 enzymes experiment
People's reconstitution cell cytochrome p 450 enzyme that use is developed by Gentest Corporation is tested needed The compounds of this invention concentration (IC when measuring different human-cytochrome P450 enzymes (2C9,2C19,3A4) 50% inhibition substrate utilization 50) experiment in vitro.These experiments comprise GentestSupersomesTM, and (the specific human cytochrome P 450 enzymes is with P450 reductase enzyme and cytochrome b 5Co expression), the concentration range of NADPH regeneration system, substrate and The compounds of this invention.Fluorescence-causing substance is the measurement terminal point of these experiments.IC 50Be to use the logarithm equation of 4 parameters to calculate, wherein the bottom is 0% to suppress, and the top be 100% suppress (when n greater than 1 the time, numerical value is average IC 50± SD).I: total experiment condition
Experiment is carried out in 96 hole microtiter plates, wherein uses the photofluorometer of Gentest Corporation development.12 holes of every row are used for one and suppress curve.The 1-8 hole comprises a series of 1: 3 diluent of test compounds.The 9-12 hole does not comprise inhibitor, and the 11st and 12 holes are the blank that is used for background fluorescence (added before enzyme stop solution).All concentration curves all carry out double.With warm reaction mixture in add enzyme and substrate, begin to carry out incubation thus., stop solution by interpolation reaction is stopped after the time at specific incubation.Use the fluorescent plate reader to measure fluorescence, measure the meta-bolites in each hole thus.The detailed experimental arrangement of each enzyme is as follows.Usually referring to being used to measure the inhibiting high output method of Cytochrome P450 (GentestCorporation, Technical Bulletin); Crespi, C.L., Miller, V.P., and Penman, B.W. (1997) Adv.Pharm.43:7-35.Ii, CYP2C9 experiment
The reaction mixture in 37 ℃ of following incubation 0.2ml/ holes 45 minutes, this mixture comprised CYP2C9 (P258), the 1.3mM NADP of 3pmol in 25mM potassiumphosphate (pH7.4) +, the G-6-P of 3.3mM, the magnesium chloride of 3.3mM, the glucose-6-phosphate dehydrogenase (G6PD) of 0.4U/ml and methoxyl group-4-trifluoromethyl tonka bean camphor of 75 μ M.CYP2C9 inhibitor with standard--sulfaphenazole carries out serial dilution by maximum concentration 10 μ M, and as positive control.Test compounds is carried out serial dilution by maximum concentration 100 μ M.Behind the incubation, reaction is stopped, using Spectra Fluor (Tecan) or Cytoflour 2350 (Millipore) fluorescent plate reader to measure the fluorescence in each hole then by the solution (80% acetonitrile/20%0.5M Tris alkali) that stops that adding 75 μ l.Use the excitation wavelength (30nm bandwidth) of 409nm and the radiation wavelength (25nm bandwidth) of 535nm respectively, perhaps the radiation wavelength (40nm bandwidth) of the excitation wavelength of 400nm (30nm bandwidth) and 460nm.Iii, CYP2C19 experiment
The reaction mixture in 37 ℃ of following incubation 0.2ml/ holes 45 minutes, this mixture comprised CYP2C19 (P258), the 1.3mM NADP of 1pmol in 50mM potassiumphosphate (pH7.4) +, the G-6-P of 3.3mM, the magnesium chloride of 3.3mM, the glucose-6-phosphate dehydrogenase (G6PD) of 0.4U/ml and 3-cyano group-7-ethoxy coumarin of 25 μ M.CYP2C19 inhibitor with standard--anti-phenyl ring amphetamine carries out serial dilution by maximum concentration 500 μ M, and as positive control.Test compounds is carried out serial dilution by maximum concentration 100 μ M.Behind the incubation, reaction is stopped, using Spectra Fluor (Tecan) fluorescent plate reader in 1 hour, to measure the fluorescence in each hole then by the solution (80% acetonitrile/20%0.5M Tris alkali) that stops that adding 75 μ l.Use the excitation wavelength (30nm bandwidth) of 409nm and the radiation wavelength (25nm bandwidth) of 465nm.Iv, CYP3A4 experiment
The reaction mixture in 37 ℃ of following incubation 0.2ml/ holes 45 minutes, this mixture comprised CYP3A4 (P258), the 1.3mM NADP of 4pmol in 200mM potassiumphosphate (pH7.4) +, 3.3mM glucose-6-phosphate dehydrogenase (G6PD), 0.01% pluronic F68 and the resorufin ethyl ether of 50 μ M of magnesium chloride, 0.4U/ml of G-6-P, 3.3mM.3A4 inhibitor with standard--KETOKONAZOL is carried out serial dilution by maximum concentration 5 μ M, and as positive control.Test compounds is carried out serial dilution by maximum concentration 100 μ M.Behind the incubation, reaction is stopped, using Spectra Fluor (Tecan) fluorescent plate reader in 1 hour, to measure the fluorescence in each hole then by the solution (80% acetonitrile/20%0.5M Tris alkali) that stops that adding 75 μ l.Use the excitation wavelength (30nm bandwidth) of 530nm and the radiation wavelength (4nm bandwidth) of 580nm.V, analysis
The fluorescent value in two holes of each concentration, the fluorescent value that does not add the fluorescent value (this be 0% suppress) in 4 holes of test compounds and 4 holes of " stopping-blank " (these holes representatives " background " are stopped because reacted) before adding enzyme average at each compound.
" % inhibition " following calculating:
100-(mean value-background of each fluorescent value) * 100/ (0% inhibition-background)
(GraphPad sets up concentration-% in Inc.) and suppresses curve at Prism.Use " Top﹠amp; Bottom Fixed " the path analysis data.Used equation is:
Y-0+100/ (1+10_ ((Log IC 50-X) * HillSlope)) wherein: X is the logarithm of concentration, and Y replys (% inhibition), in 0% beginning, and advances to 100%, has the S shape.
This equation is for " four parameter logarithm equatioies ".Vi, result
Test compounds is shown in Table 2 the average IC50 value of the metabolite formation of different CYP enzyme mediations.Use is for the known inhibitor of the CYP of each analysis (positive control), and experimental value is effective.If the IC of positive control 50Value thinks that then experiment is effective for the content in the table 2 within 1 standard deviation of the history average of CYP positive control.If the IC of positive control 50Value then should be tested eliminating outside 1 standard deviation.B, anoxic scheme
Anoxic contact (10.0 ± 0.5%O 2) be that (New York realizes in USA) for Manostat, Brooklyn by rat being placed on 3301 Plexiglas glove boxes.Discontinuously by in this glove box, adding nitrogen in the liquid nitrogen holder.Baralyme (Allied Health Care Products, St.Louis, Missouri, USA) CO 2Washer is with CO 2Concentration keeps below 0.2%.Relative humidity in the glove box keeps below 70% with anhydrous calciumsulphate.Use boric acid, with the NH in the glove box 3It is minimum that concentration keeps.Referring to: people such as Tilton (2000) Pulm.Pharm.Ther.13:87-97.I, acute anoxia scheme
In initial experiment, the assessment test compounds is to the effect of the mean pulmonary arterial pressure (MPAP) that is exposed to 90 minutes rat of acute anoxia environment subsequently.Under vetanarcol anesthesia (50mg/kgip), femoral artery and vein are carried out intubate, and by right jugular vein pulmonary artery is carried out intubate with the thoracic cavity sealing technique.All intubate all are connected on polyethylene (PE 20) pipe, and guide to the outside by the subcutaneous Stainless Steel Wire of imbedding (diameter is 0.018in) at the rear side of neck.After 2 days, write down MPAP by the transverter that is connected on the multiple ripple tracer by thigh and pulmonary artery intubate.In case reach stable recording curve, just make clear-headed and unconstrained rat contact anaerobic environment (10%O 2, 1atm), and in 90 minutes time, write down the influence of anoxic to this parameter.In experimental design, insert test compounds and prevent scheme (iv infusion 5mg/kg in 10 minutes time, stopped in preceding 10 minutes in the beginning anoxic) and test compounds jamming program (iv infusion 5mg/kg in 10 minutes time started after the beginning anoxic in 50 minutes).Ii, result
Acute normobaric anoxic increases relevant with the two-phase (biphasic) of MPAP: the baseline values by 19mm Hg in 5 minutes increases to 24.5mm Hg, dropped to 21mm Hg then in ensuing 10 minutes, then the anoxic of coming in remainder is back to the peak level of about 25mm Hg in the time.When this group came back to room air when experiment finishes, lung pressed rapid return to baseline value.As shown in table 2, when being lower than the required dosage of known endothelium peptide, compound of the present invention is effective for suppressing the vasoconstriction that anoxic brings out.
Because some modifications it will be apparent to those skilled in the art that, therefore limited by appended claim to the present invention.

Claims (75)

1, with the compound of following formula IV:
Figure A0081806100021
Or acceptable derivates on its pharmacology, wherein:
X be S or-C (R 3)=C (R 4)-;
R 1Be halogen or low alkyl group;
R 2It is low alkyl group;
R 3And R 4Be independently selected from hydrogen, halogen, cyano group, cyano group alkyl, C (O) R 41, alkyl, alkenyl, cycloalkyl and aryl, or form alkylidene group or alkenylene, wherein R together 41Be alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkyl amido, arylamino, ammonia diaryl base, alkyl sulfonyl-amino, arlysulfonylamino, alkyl sulphonyl alkylamino, alkyl sulphonyl arylamino, aryl sulfonyl alkylamino or aryl sulfonyl arylamino;
R 5Be low alkyl group or-(CH 2) xC (O) (CH 2) yCH 3
R 6Be low alkyl group ,-(CH 2) xC (O) (CH 2) yCH 3, or heteroaryl;
R 7Be hydrogen, hydroxyl, alkoxyl group, low alkyl group, S (O) 2NHR 50And OS (O) 2NR 38R 39
R wherein 38And R 39Be independently selected from respectively in hydrogen, alkyl, alkenyl, alkynyl group, aryl, haloalkyl, alkylaryl, heterocyclic radical, arylalkyl, alkoxy aryl, alkoxyl group, aryloxy, cycloalkyl, cycloalkenyl group and cycloalkynyl radical;
X and y are respectively 0-14 independently;
R 50Be hydrogen, low alkyl group, lower alkoxy or heteroaryl;
Y and R 8Following being selected from (i) or (ii):
(i) Y is O; And R 8Be CONR 38R 39, CN, heteroaryl, alkyl sulphonyl, (CH 2) xC (O) (CH 2) yCH 3, alkyl, halogen, pseudohalogen, hydroxyalkyl, C (O) (CH 2) xS (O) 2(CH 2) yCH 3Or C (=N-OR 38) (CH 2) yCH 3Perhaps
(ii) Y and R 8Form 3-16 unit not replacement or substituted ring or heterocycle with the atom that they connected;
R 9Be H;
Y 1And Y 2Be respectively carbon or nitrogen independently;
If Y 2Be carbon, then a is 1; If Y 2Be nitrogen, then a is 0;
If Y 1Be carbon, then b is 1; If Y 1Be nitrogen, then b is 0; And
W is NH.
2, compound as claimed in claim 1, wherein:
X is S; R 3And R 4Be respectively H; Y 1And Y 2Be respectively carbon; And a and b are respectively 1.
3, compound as claimed in claim 1, wherein this compound has formula V:
Figure A0081806100041
And acceptable derivates on the pharmacology, wherein:
X be S or-CH=CH-;
R 1Be halogen or low alkyl group;
R 2It is low alkyl group;
R 3And R 4Be respectively hydrogen;
R 5Be low alkyl group or-(CH 2) xC (O) (CH 2) yCH 3R 6Be low alkyl group ,-(CH 2) xC (O) (CH 2) yCH 3, or heteroaryl;
R 7Be selected from following group: hydrogen, hydroxyl, alkoxyl group, low alkyl group, S (O) 2NHR 50And OS (O) 2NR 38R 39
R 38And R 39Be independently selected from hydrogen alkyl, alkenyl, alkynyl group, aryl, haloalkyl, alkylaryl, heterocyclic radical, arylalkyl, alkoxy aryl, alkoxyl group, aryloxy, cycloalkyl, cycloalkenyl group and cycloalkynyl radical respectively;
X and y are respectively 0-14 independently;
R 50Be hydrogen, low alkyl group, lower alkoxy or heteroaryl;
Y and R 8Following being selected from (i) or (ii):
(i) Y is O; And R 8Be CONR 38R 39, CN, heteroaryl, alkyl sulphonyl, (CH 2) yC (O) (CH 2) yCH 3, alkyl, halogen, pseudohalogen, hydroxyalkyl, C (O) (CH 2) xS (O) 2(CH 2) yCH 3Or C (=N-OR 38) (CH 2) yCH 3Perhaps
(ii) Y and R 8Form 3-16 unit not replacement or substituted ring or heterocycle with the atom that they connected;
R 9Be H;
Y 1And Y 2Be respectively carbon or nitrogen independently;
If Y 2Be carbon, then a is 1; If Y 2Be nitrogen, then a is 0;
If Y 1Be carbon, then b is 1; If Y 1Be nitrogen, then b is 0; And
W is NH.
4, compound as claimed in claim 3, wherein R 1Be Cl or Me; And R 2Be Me.
5, compound as claimed in claim 3, wherein:
R 5Be Me or ethanoyl;
R 6Be Me, ethanoyl or 2-oxazolyl;
R 7Be H, Me, OSON 2Me 2, OCH 2-cyclopropyl, hydroxyl or SO 2NH-(4-chloro-3-methyl-5-isoxazolyl);
Y and R 8Following being selected from (i) or (ii):
(i) Y is O; And R 8Be C (O) CH 2SO 2CH 3, C (O) Me, CN, C (O) N (Me) (CH 2-t-Bu), SO 2Me, 2-oxazolyl, SO 2-sec.-propyl, SO 2-n-propyl group, CH (OH) Me, C (O) NMe 2, C (=N-OMe) Me, Me, C (O) Et, Cl, n-propyl group or ethyl; Perhaps
(ii) Y and R 8Together formation-CO-N=or-CO-C (CN)=;
R 9Be H;
Y 1And Y 2Be respectively carbon or nitrogen independently;
If Y 2Be carbon, then a is 1; If Y 2Be nitrogen, then a is 0;
If Y 1Be carbon, then b is 1; If Y 1Be nitrogen, then b is 0; And
W is NH.
6, compound as claimed in claim 3, wherein:
X is S;
R 1Be Cl or Me;
R 2Be Me;
R 3, R 4And R 9Be H;
Y is O;
W is NH; And
Y 1And Y 2Be respectively carbon.
7, compound as claimed in claim 6, wherein this compound has formula VI:
Figure A0081806100071
Or acceptable derivates on its pharmacology, wherein:
R 1Be Cl or Me;
R 5Be Me or ethanoyl;
R 6Be Me, ethanoyl or 2-oxazolyl;
R 7Be H, Me, OSO 2NMe 2, OCH 2-cyclopropyl, hydroxyl or SO 2NH-(4-chloro-3-methyl-5-isoxazolyl); And
R 8Be C (O) CH 2SO 2CH 3, C (O) Me, CN, C (O) N (Me) (CH 2-t-Bu), SO 2Me, 2-oxazolyl, SO 2-sec.-propyl, SO 2-n-propyl group, CH (OH) Me, C (O) NMe 2, C (=N-OMe) Me, Me, C (O) Et, Cl, n-propyl group or ethyl.
8, compound as claimed in claim 7, wherein R 1, R 5And R 6Be Me; And R 7Be hydrogen.
9, compound as claimed in claim 1, it is selected from following group: N-(2-ethanoyl-4, the 6-3,5-dimethylphenyl)-3-{[(3,4 dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-2-thiophenecarboxamides, N-(2-cyano group-3,4, the 6-trimethylphenyl)-and 3-{[(3,4-dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-2-thiophenecarboxamides, 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(3; 4; 6-trimethylammonium-2-propionyl phenyl)-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-[2-(1-hydroxyethyl)-4; the 6-3,5-dimethylphenyl]-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the N-{2-[(dimethylamino) carbonyl]-4; the 6-3,5-dimethylphenyl)-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-{2; 4-dimethyl-6-[(methyl oxygen base) ethanimidoyl] phenyl }-the 2-thiophenecarboxamides; 3-{[(3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-sulfur phenenyl) carbonyl] amino }-2; 4; 6-trimethylphenyl-N; N-dimethylamino sulphonate; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-{3-[(cyclopropyl methyl) the oxygen base]-2; 4; the 6-trimethylphenyl }-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2; 4; 6-trimethylammonium-5-pyrimidyl)-the 2-thiophenecarboxamides; N-(2-ethanoyl-3; 4; the 6-trimethylphenyl)-and 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2-cyano group-3; 4; the 6-trimethylphenyl)-the 2-thiophenecarboxamides; N-(2-chloro-4; the 6-3,5-dimethylphenyl)-and 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(4; 6-diacetyl-3-hydroxyl-2-propyl group phenyl-2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2; 4-dimethyl-6-[2-(methyl sulphonyl) ethanoyl] phenyl }-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2; 4-dimethyl-6-{[methyl (2; the 2-dimethyl propyl) amino] carbonyl } phenyl)-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl)-N-[2; 4-dimethyl-6-(methyl sulphonyl) phenyl]-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-[2; 4-dimethyl-6-(1; 3-oxazole-2-yl) phenyl]-the 2-thiophenecarboxamides; 3-{[(4-chloro-5-isoxazolyl) amino] alkylsulfonyl }-N-[2-(2-sulfonyl propyl base)-4; the 6-3,5-dimethylphenyl]-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl)-N-[2; 4-dimethyl-6-(sulfonyl propyl base) phenyl]-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2-ethyl-4; the 6-3,5-dimethylphenyl)-the 2-thiophenecarboxamides; 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-[2; 6-dimethyl-4-(1; 3-oxazole-2-yl) phenyl]-the 2-thiophenecarboxamides; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6; 8-dimethyl-4-hydroxyl-2-benzo pyrimidyl) thiophene-3-sulphonamide and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyano group-4-hydroxyl-6; 8-dimethylbiphenyl [b] pyridine-2-yl) thiophene-3-sulphonamide, or acceptable derivates on its pharmacology.
10, compound as claimed in claim 1, it is N-(2-ethanoyl-4,6-3,5-dimethylphenyl)-3-{[(3,4-dimethyl-5-isoxazolyl) amino] alkylsulfonyl }-the 2-thiophenecarboxamides, or acceptable derivates on its pharmacology.
11, acceptable salt on a kind of pharmacology, it comprises compound as claimed in claim 10.
12, salt as claimed in claim 11, it is a sodium salt.
13, compound as claimed in claim 1, wherein Y 1And Y 2Be respectively nitrogen.
14, compound as claimed in claim 13, wherein a and b are respectively 0.
15, compound as claimed in claim 13, wherein R 5, R 6And R 8It is alkyl; Y is O; And W is NH.
16, compound as claimed in claim 13, wherein R 3And R 4Be respectively H; And X is S.
17, compound as claimed in claim 13, it is 3-{[(4-chloro-3-methyl-5-isoxazolyl) amino] alkylsulfonyl }-N-(2,4,6-trimethylammonium-5-pyrimidyl)-2-thiophenecarboxamides, or acceptable derivates on its pharmacology.
18, compound as claimed in claim 1, wherein X is-C (R 3)=C (R 4)-.
19, compound as claimed in claim 18, it has formula VII:
Figure A0081806100101
And acceptable derivates on the pharmacology, wherein R 1And R 2Be following (i), (ii) or (iii):
(i) R 1And R 2Be independently selected from respectively in H, NH 2, NO 2Halogen; pseudohalogen; alkyl; alkenyl; alkynyl group; aryl; arylalkyl; heteroaryl; alkoxyl group; alkylamino; alkylthio; alkyl oxy; haloalkyl; the alkyl sulfinyl; alkyl sulphonyl; aryloxy; arylamino; arylthio; the aryl sulfinyl; aryl sulfonyl; haloalkyl; the halogen aryl; alkoxy carbonyl; alkyl-carbonyl; aminocarboxyl; aryl carbonyl; formyl radical; replace or the sunsubstituting formyl amine base; to replace or not replace urea groups; alkyl wherein; alkenyl and alkynyl group partly comprise 1-14 carbon atom; and can be straight or branched or cyclic; and aryl moiety comprises about 4-16 carbon atom, but R 2Not halogen or pseudohalogen; Perhaps
(ii) R 1And R 2Formation-(CH together 2) n-, wherein n is 3-6; Perhaps
(iii) R 1And R 2Form the 1,3-butadiene base together (CH=CH-CH=CH-);
W is O, NH or (CH 2) zWherein z is 0-6; And Y is O, S, perhaps with R 8And the atom that they connected forms 3-16 unit not replacement or substituted ring or heterocycle together;
R 3And R 4Be independently selected from hydrogen, halogen, cyano group, cyano group alkyl, C (O) R 41, alkyl, alkenyl, cycloalkyl and aryl, or form alkylidene group or alkenylene, wherein R together 41Be alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkyl amido, arylamino, ammonia diaryl base, alkyl sulfonyl-amino, arlysulfonylamino, alkyl sulphonyl alkylamino, alkyl sulphonyl arylamino, aryl sulfonyl alkylamino or aryl sulfonyl arylamino;
Y 1And Y 2Be respectively carbon or nitrogen independently; A and b are respectively 0 or 1 independently;
R 5, R 6, R 7, R 8And R 9Following independently respectively be selected from (i) or (ii):
(i) R 5, R 6, R 7, R 8And R 9Be independently selected from H OH, NHR respectively 38, CONR 38R 39, NO 2, cyano group, halogen, pseudohalogen, alkyl; alkenyl, alkynyl group, aryl, arylalkyl, heteroaryl; alkoxyl group, alkylamino, alkylthio, haloalkyl, alkyl sulfinyl; alkyl sulphonyl, alkoxy carbonyl, alkyl-carbonyl, thiazolinyl sulfenyl; alkenyl amino, alkenyl oxy, alkenyl sulfinyl, alkenyl alkylsulfonyl; alkoxy carbonyl, aromatic yl aminocarbonyl, alkyl amino-carbonyl, aminocarboxyl; (alkyl-aminocarboxyl) alkyl, acetoxyl group, hydroxyl, carboxyl; carboxyalkyl, carboxyl alkenyl, alkyl sulfonyl-amino alkyl, cyano group alkyl; ethanoyl, acetoxyl group alkyl, hydroxyalkyl, alkoxyl group alkoxyl group; hydroxyalkyl, (acetoxyl group) alkoxyl group, (hydroxyl) alkoxyl group, formyl radical; SULPHURYL CHLORIDE, amino acid, hexose, O-glycosides; ribose, low alkyl group, CN ,-(CH 2) xC (O) (CH 2) yCH 3,-(CH 2) xCH 3, (CH 2) xThe NH-low alkyl group ,-(CH 2) xC (O) NH 2, D-, L-or DL-Amino Acid, uncle or secondary amide, O-glycosides, hexose or ribose ,-S (O) 2NH 2, hydroxyl, alkoxyl group, alkoxy carbonyl, acetoxyl group alkyl ,-(CH 2) xCOOH ,-(CH 2) xCH (COOH) (CH 2) yCH 3, CO 2-low alkyl group, CN, heteroaryl, C (O) (CH 2) xS (O) 2(CH 2) yCH 3, C (=N-OR 38) (CH 2) yCH 3,-C (O) C (O) (CH 2) yCH 3,-(CH 2) xN (CH 3) 2, S (O) 2NHR 50, OS (O) 2NR 38R 39, alkylaryl, miscellaneous alkyl aryl, C (O) NHR 50,-(CH 2) xOH and-C (O) N (H) N (H) R 50
R wherein 38And R 39Be independently selected from hydrogen alkyl, alkenyl, alkynyl group, aryl, haloalkyl, alkylaryl, heterocyclic radical, arylalkyl, alkoxy aryl, alkoxyl group, aryloxy, cycloalkyl, cycloalkenyl group and cycloalkynyl radical respectively;
X and y are respectively 0-14 independently;
R 50It is substituting group such as hydrogen, low alkyl group, lower alkoxy or heteroaryl; Perhaps
The (ii) R of the adjacent carbons on the substituted ring 5, R 6, R 7, R 8And R 9In at least two form alkylenedioxy group, alkylidene group sulfo-oxygen base oxygen base or alkylidene group dithio oxygen base together, these groups are not replace or be substituted by replacing one or more hydrogen with halogen, low alkyl group, lower alkoxy or junior alkyl halides, and other R 5, R 6, R 7, R 8And R 9Select as (i).
20, compound as claimed in claim 19, wherein R 3, R 4And R 9Be H; Y is O; And W is NH.
21, compound as claimed in claim 19, wherein R 1And R 2Be independently selected from respectively in alkyl, low-grade alkenyl, alkynyl of low-grade chain, low-grade halogenated alkyl, halogen, pseudohalogen or H, but R 2It or not halogen.
22, compound as claimed in claim 19, wherein R 1Be low alkyl group or halogen; And R 2It is low alkyl group.
23, compound as claimed in claim 19, wherein this compound has formula VIII:
Figure A0081806100131
Or acceptable derivates on its pharmacology, wherein:
R 1Be low alkyl group or halogen;
R 5Be low alkyl group or-(CH 2) xC (O) (CH 2) yCH 3
R 6Be low alkyl group ,-(CH 2) xC (O) (CH 2) yCH 3, or heteroaryl;
R 7Be hydrogen, hydroxyl, alkoxyl group, low alkyl group, S (O) 2NHR 50Or OS (O) 2NR 38R 39And
R 8Be CONR 38R 39, CN, heteroaryl, alkyl sulphonyl, (CH 2) xC (O) (CH 2) yCH 3, alkyl, halogen, pseudohalogen, hydroxyalkyl, C (O) (CH 2) xS (O) 2(CH 2) yCH 3Or C (=N-OR 38) (CH 2) yCH 3
24, compound as claimed in claim 23, wherein:
R 5Be Me or ethanoyl;
R 6Be Me, ethanoyl or 2-oxazolyl;
R 7Be H, Me, OSO 2NMe 2, OCH 2-cyclopropyl, hydroxyl or SO 2NH-(4-chloro-3-methyl-5-isoxazolyl); And
R 8Be C (O) CH 2SO 2CH 3, C (O) Me, CN, C (O) N (Me) (CH 2-t-Bu), SO 2Me, 2-oxazolyl, SO 2-sec.-propyl, SO 2-n-propyl group, CH (OH) Me, C (O) NMe 2, C (=N-OMe) Me, Me, C (O) Et, Cl, n-propyl group or ethyl.
25, compound as claimed in claim 23, wherein R 5And R 6Be Me; R 7Be H; And R 8Be C (O) Me.
26, compound as claimed in claim 23, it is N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-ethanoyl-4,6-3,5-dimethylphenyl aminocarboxyl) benzsulfamide.
27, compound as claimed in claim 1, wherein M is (CH 2) z, wherein z is 0-6.
28, compound as claimed in claim 27, wherein this compound has formula X: Or acceptable derivates, wherein R on its pharmacology 1And R 2Be following (i), (ii) or (iii):
(i) R 1And R 2Be independently selected from respectively in H, NH 2, NO 2Halogen; pseudohalogen; alkyl; alkenyl; alkynyl group; aryl; arylalkyl; heteroaryl; alkoxyl group; alkylamino; alkylthio; alkyl oxy; haloalkyl; the alkyl sulfinyl; alkyl sulphonyl; aryloxy; arylamino; arylthio; the aryl sulfinyl; aryl sulfonyl; haloalkyl; the halogen aryl; alkoxy carbonyl; alkyl-carbonyl; aminocarboxyl; aryl carbonyl; formyl radical; replace or the sunsubstituting formyl amine base; and replace or do not replace urea groups; alkyl wherein; alkenyl and alkynyl group partly comprise 1-14 carbon atom; and can be straight or branched or cyclic; and aryl moiety comprises about 4-16 carbon atom, but R 2Not halogen or pseudohalogen; Perhaps
(ii) R 1And R 2Formation-(CH together 2) n-, wherein n is 3-6; Perhaps
(iii) R 1And R 2Form the 1,3-butadiene base together (CH=CH-CH=CH-);
Y 1And Y 2Be respectively carbon or nitrogen independently; A and b are respectively 0 or 1 independently;
R 5, R 6, R 7, R 8And R 9Following independently respectively be selected from (i) or (ii):
(i) R 5, R 6, R 7, R 8And R 9Be independently selected from H OH, NHR respectively 38, CONR 38R 39, NO 2, cyano group, halogen, pseudohalogen, alkyl; alkenyl, alkynyl group, aryl, arylalkyl, heteroaryl; alkoxyl group, alkylamino, alkylthio, haloalkyl, alkyl sulfinyl; alkyl sulphonyl, alkoxy carbonyl, alkyl-carbonyl, thiazolinyl sulfenyl; alkenyl amino, alkenyl oxy, alkenyl sulfinyl, alkenyl alkylsulfonyl; alkoxy carbonyl, aromatic yl aminocarbonyl, alkyl amino-carbonyl, aminocarboxyl; (alkyl-aminocarboxyl) alkyl, acetoxyl group, hydroxyl, carboxyl; carboxyalkyl, carboxyl alkenyl, alkyl sulfonyl-amino alkyl, cyano group alkyl; ethanoyl, acetoxyl group alkyl, hydroxyalkyl, alkoxyl group alkoxyl group; hydroxyalkyl, (acetoxyl group) alkoxyl group, (hydroxyl) alkoxyl group, formyl radical; SULPHURYL CHLORIDE, amino acid, hexose, O-glycosides; ribose, low alkyl group, CN ,-(CH 2) xC (O) (CH 2) yCH 3,-(CH 2) xCH 3, (CH 2) xThe NH-low alkyl group ,-(CH 2) xC (O) NH 2, D-, L-or DL-Amino Acid, uncle or secondary amide, O-glycosides, hexose or ribose ,-S (O) 2NH 2, hydroxyl, alkoxyl group, alkoxy carbonyl, acetoxyl group alkyl ,-(CH 2) xCOOH ,-(CH 2) xCH (COOH) (CH 2) yCH 3, CO 2-low alkyl group, CN, heteroaryl, C (O) (CH 2) xS (O) 2(CH 2) yCH 3, C (=N-OR 38) (CH 2) yCH 3,-C (O) C (O) (CH 2) yCH 3,-(CH 2) xN (CH 3) 2, S (O) 2NHR 50, OS (O) 2NR 38R 39, alkylaryl, miscellaneous alkyl aryl, C (O) NHR 50,-(CH 2) xOH and-C (O) N (H) N (H) R 50
R wherein 38And R 39Be independently selected from hydrogen alkyl, alkenyl, alkynyl group, aryl, haloalkyl, alkylaryl, heterocyclic radical, arylalkyl, alkoxy aryl, alkoxyl group, aryloxy, cycloalkyl, cycloalkenyl group and cycloalkynyl radical respectively; X and y are respectively 0-14 independently; And R 50Be hydrogen, low alkyl group, lower alkoxy or heteroaryl; Perhaps
The (ii) R of the adjacent carbons on the substituted ring 5, R 6, R 7, R 8And R 9In at least two form alkylenedioxy group, alkylidene group sulfo-oxygen base oxygen base or alkylidene group dithio oxygen base together, these groups are not replace or be substituted by replacing one or more hydrogen with halogen, low alkyl group, lower alkoxy or junior alkyl halides, and other R 5, R 6, R 7, R 8And R 9Select as (i).
29, compound as claimed in claim 28, wherein:
R 1Be halogen or low alkyl group;
R 2It is low alkyl group;
R 5Be low alkyl group or-(CH 2) xC (O) (CH 2) yCH 3
R 6Be low alkyl group ,-(CH 2) xC (O) (CH 2) yCH 3, or heteroaryl;
R 7Be hydrogen, hydroxyl, alkoxyl group, low alkyl group, S (O) 2NHR 50And OS (O) 2NR 38R 39
R wherein 38And R 39Be independently selected from respectively in hydrogen, alkyl, alkenyl, alkynyl group, aryl, haloalkyl, alkylaryl, heterocyclic radical, arylalkyl, alkoxy aryl, alkoxyl group, aryloxy, cycloalkyl, cycloalkenyl group and cycloalkynyl radical; X and y are respectively 0-14 independently; And R 50Be hydrogen, low alkyl group, lower alkoxy or heteroaryl;
R 8Be CONR 38R 39, CN, heteroaryl, alkyl sulphonyl, (CH 2) xC (O) (CH 2) yCH 3, alkyl, halogen, pseudohalogen, hydroxyalkyl, C (O) (CH 2) xS (O) 2(CH 2) yCH 3Or C (=N-OR 38) (CH 2) yCH 3
R 9Be H; Y 1And Y 2Be respectively carbon or nitrogen independently; If Y 2Be carbon, then a is 1; If Y 2Be nitrogen, then a is 0; If Y 1Be carbon, then b is 1; And if Y 1Be nitrogen, then b is 0.
30, compound as claimed in claim 29, wherein Y 1And Y 2Be carbon; A and b are respectively 1; R 5, R 6And R 8It is low alkyl group; And R 7Be H or SO 2NHR 50, R wherein 50It is heteroaryl.
31, compound as claimed in claim 28; it is selected from following group: N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2; 4; the 6-trimethyl benzyl) benzo [b] thiophene-3-sulphonamide and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(4-chloro-3-methyl-5-isoxazolyl) amino-sulfonyl-2; 4, the 6-trimethyl benzyl) benzo [b] thiophene-3-sulphonamide.
32, acceptable salt on the pharmacology of compound as claimed in claim 1.
33, salt as claimed in claim 32, it is a sodium salt.
34, a kind of pharmaceutical composition, it comprises acceptable derivates on the compound as claimed in claim 1 in the acceptable carrier on pharmacology of significant quantity or its pharmacology, wherein, described amount can effectively be improved the symptom of the disease that the endothelium peptide regulated.
35, a kind of pharmaceutical composition, it comprises acceptable derivates on the compound as claimed in claim 10 in the acceptable carrier on pharmacology of significant quantity or its pharmacology, wherein, described amount can effectively be improved the symptom of the disease that the endothelium peptide regulated.
36, composition as claimed in claim 34, it is single dose or many doses formulation.
37, composition as claimed in claim 35, it is single dose or many doses formulation.
38, a kind of finished product, it comprises wrapping material, be included in acceptable derivates on compound as claimed in claim 1 in these wrapping material or its pharmacology, wherein, described compound is the effect of antagonism endothelium peptide effectively, effectively improve the symptom of endothelin-mediated disorder, perhaps the IC below about 10 μ M 50The time suppress the keying action of endothelium peptide and ET acceptor, and described wrapping material comprise label, this label illustrates that this compound or derivatives thereof is used for the keying action of antagonism endothelium peptide effect, treatment endothelin-mediated disorder or inhibition skin peptide and ET acceptor.
39, a kind of finished product, it comprises wrapping material, be included in acceptable derivates on compound as claimed in claim 10 in these wrapping material or its pharmacology, wherein, described compound is the effect of antagonism endothelium peptide effectively, effectively improve the symptom of endothelin-mediated disorder, perhaps the IC below about 10 μ M 50The time suppress the keying action of endothelium peptide and ET acceptor, and described wrapping material comprise label, this label illustrates that this compound or derivatives thereof is used for the keying action of antagonism endothelium peptide effect, treatment endothelin-mediated disorder or inhibition skin peptide and ET acceptor.
40, a kind of method for the treatment of the disease that the endothelium peptide regulated, it comprises acceptable derivates on the compound as claimed in claim 1 of patient's effective dosage or its pharmacology, wherein, described significant quantity is enough to alleviate the symptom of one or more described diseases.
41, a kind of method for the treatment of the disease that the endothelium peptide regulated, it comprises acceptable derivates on the compound as claimed in claim 10 of patient's effective dosage or its pharmacology, wherein, described significant quantity is enough to alleviate the symptom of one or more described diseases.
42, method as claimed in claim 40, wherein, described disease is selected from: hypertension, cardiovascular disorder, heart trouble comprises myocardial infarction, pulmonary hypertension, new natural disposition pulmonary hypertension, the hypertension that erythropoietin is regulated, respiratory disease and inflammation comprise asthma, bronchoconstriction, eye disease comprises that glaucoma and retina perfusion are insufficient, gastrointestinal illness, renal failure, endotoxin shock, the menstruation disease, obstetrics' disease, injured, the plate inflammation, erective dysfunction, menopause, osteoporosis and bone metabolic disease, the weather disease comprises hot flush, unusual grumeleuse behavior, the sickness rate of urethra reproductive tract discomfort and cardiovascular disorder increases, with other and middle-aged women ovarian function decline diseases associated, preeclampsia, the control of gestation time, the disease that nitrogen oxide weakens, anaphylactic shock, hemorrhagic shock, and the kidney vasoconstriction of immunosuppressor mediation.
43, method as claimed in claim 41, wherein, described disease is selected from: hypertension, cardiovascular disorder, heart trouble comprises myocardial infarction, pulmonary hypertension, new natural disposition pulmonary hypertension, the hypertension that erythropoietin is regulated, respiratory disease and inflammation comprise asthma, bronchoconstriction, eye disease comprises that glaucoma and retina perfusion are insufficient, gastrointestinal illness, renal failure, endotoxin shock, the menstruation disease, obstetrics' disease, injured, the plate inflammation, erective dysfunction, menopause, osteoporosis and bone metabolic disease, the weather disease comprises hot flush, unusual grumeleuse behavior, the sickness rate of urethra reproductive tract discomfort and cardiovascular disorder increases, with other and middle-aged women ovarian function decline diseases associated, preeclampsia, the control of gestation time, the disease that nitrogen oxide weakens, anaphylactic shock, hemorrhagic shock, and the kidney vasoconstriction of immunosuppressor mediation.
44, method as claimed in claim 42, wherein, described disease is selected from asthma and inflammation.
45, method as claimed in claim 42, wherein, described disease is a glaucoma.
46, method as claimed in claim 43, wherein, described disease is selected from asthma and inflammation.
47, method as claimed in claim 43, wherein, described disease is a glaucoma.
48, a kind of inhibition endothelium peptide and endothelium peptide A(ET A) or the endothelium peptide B(ET B) method of receptors bind, it comprises makes described acceptor contact with acceptable derivates on compound as claimed in claim 1 or its pharmacology, wherein:
Described contact described acceptor with before the endothelium peptide contacts, with its simultaneously or carry out thereafter.
49, a kind of inhibition endothelium peptide and endothelium peptide A(ET A) or the endothelium peptide B(ET B) method of receptors bind, it comprises makes described acceptor contact with acceptable derivates on compound as claimed in claim 10 or its pharmacology, wherein:
Described contact described acceptor with before the endothelium peptide contacts, with its simultaneously or carry out thereafter.
50, the active method of a kind of change endothelium peptide acceptor adjusting, it comprises makes endothelium peptide acceptor contact with acceptable derivates on compound as claimed in claim 1 or its pharmacology.
51, the active method of a kind of change endothelium peptide acceptor adjusting, it comprises makes endothelium peptide acceptor contact with acceptable derivates on compound as claimed in claim 10 or its pharmacology.
52, pharmaceutical composition as claimed in claim 34, acceptable carrier comprises the sodium phosphate buffer that contains sugar on the wherein said pharmacology.
53, pharmaceutical composition as claimed in claim 52, wherein said compound are acceptable an alkali metal salts on the pharmacology.
54, a kind of lyophilized powder, it comprises the salt of compound as claimed in claim 1.
55, lyophilized powder as claimed in claim 54, it is prepared as follows:
(a) acceptable salt is dissolved in the sodium phosphate buffer that comprises sugar or carbohydrate on the pharmacology with described sulfonamide compounds;
(b) solution of sterile filtration gained; With
(c) the filtered solution of freeze-drying under standard conditions, the preparation sterilized powder.
56, lyophilized powder as claimed in claim 55, wherein, described sugar or carbohydrate are glucose.
57, a kind of finished product, it comprises wrapping material, is included in the lyophilized powder as claimed in claim 54 in these wrapping material, and wherein, described compound is the effect of antagonism endothelium peptide effectively, effectively improve the symptom of endothelin-mediated disorder, perhaps the IC below about 1 μ M 50The time suppress the keying action of endothelium peptide and ET acceptor, and described wrapping material comprise label, and this label illustrates that acceptable salt on this compound or its pharmacology is used for antagonism endothelium peptide effect, treatment endothelin-mediated disorder or suppresses the keying action of skin peptide and ET acceptor.
58, a kind of combination, it comprises the aseptic phial that contains the lyophilized powder described just like claim 54.
59, combination as claimed in claim 58, wherein, the amount that described aseptic phial comprises powder is single dosage.
60, combination as claimed in claim 58, wherein, described aseptic phial also comprises a certain amount of Injectable sterile water, and the ultimate density of described sulphonamide sodium salt is between about 1-250mg/ml.
61, pharmaceutical composition as claimed in claim 34, it is shaped to tablet or capsule.
62, pharmaceutical composition as claimed in claim 61, it further comprises enteric coating.
63, pharmaceutical composition as claimed in claim 61, wherein, described dressing is selected from Cellacefate, polyoxyethylene glycol, polyethenoxy sorbitan, Viscotrol C, ethyl cellulose pseudolatex, salol, n-butyl stearate, stearic acid and carnauba wax.
64, pharmaceutical composition as claimed in claim 35, acceptable carrier comprises the sodium phosphate buffer that contains sugar on the wherein said pharmacology.
65, as the described pharmaceutical composition of claim 64, wherein said compound is an acceptable an alkali metal salt on the pharmacology.
66, a kind of lyophilized powder, it comprises the salt of compound as claimed in claim 10.
67, as the described lyophilized powder of claim 66, it is prepared as follows:
(a) acceptable salt is dissolved in the sodium phosphate buffer that comprises sugar or carbohydrate on the pharmacology with described sulfonamide compounds;
(b) solution of sterile filtration gained; With
(c) the filtered solution of freeze-drying under standard conditions, the preparation sterilized powder.
68, as the described lyophilized powder of claim 67, wherein, described sugar or carbohydrate are glucose.
69, a kind of finished product, it comprises wrapping material, be included in these wrapping material as the described lyophilized powder of claim 66, wherein, described compound is the effect of antagonism endothelium peptide effectively, effectively improve the symptom of endothelin-mediated disorder, perhaps the IC below about 1 μ M 50The time suppress the keying action of endothelium peptide and ET acceptor, and described wrapping material comprise label, and this label illustrates that acceptable salt on this compound or its pharmacology is used for antagonism endothelium peptide effect, treatment endothelin-mediated disorder or suppresses the keying action of skin peptide and ET acceptor.
70, a kind of combination, it comprises the aseptic phial that contains the lyophilized powder described just like claim 66.
71, as the described combination of claim 70, wherein, the amount that described aseptic phial comprises powder is a single dose.
72, as the described combination of claim 70, wherein, described aseptic phial also comprises a certain amount of Injectable sterile water, and the ultimate density of described sulphonamide sodium salt is between about 1-250mg/ml.
73, pharmaceutical composition as claimed in claim 35, it is shaped to tablet or capsule.
74, as the described pharmaceutical composition of claim 73, it further comprises enteric coating.
75, as the described pharmaceutical composition of claim 73, wherein, described dressing is selected from Cellacefate, polyoxyethylene glycol, polyethenoxy sorbitan, Viscotrol C, ethyl cellulose pseudolatex, salol, n-butyl stearate, stearic acid and carnauba wax.
CN00818061A 1999-12-31 2000-12-29 Sulfonamides and derivatives thereof that modulate the activeity of endothelin Pending CN1414965A (en)

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